Seventeenth Interim Report of the Committee on Acute Exposure Guideline Levels

BACKGROUND

In 1991, the U.S. Environmental Protection Agency (EPA) and the Agency for Toxic Substances and Disease Registry (ATSDR) asked the National Research Council to provide technical guidance for establishing community emergency exposure levels (CEELs) for extremely hazardous substances (EHSs) pursuant to the Superfund Amendments and Reauthorization Act of 1986. 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) on Acute Exposure Guideline Levels for Hazardous Substances.

The NAC was established to identify, review, and interpret relevant toxicologic and other scientific data and to develop acute exposure guideline levels (AEGLs) for high-priority, acutely toxic chemicals. AEGLs developed by the NAC have a broad array of potential applications for federal, state, and local governments and for the private sector. AEGLs are needed for prevention of and emergency-response planning for potential releases of EHSs caused by accidents or terrorist activities.

AEGLs are threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 min to 8 h. Three levels designated as AEGL-1, AEGL-2 and AEGL-3 are developed for each of five exposure periods (10 and 30 min, 1, 4, and 8 h) and are distinguished by degree of severity of toxic effects. The three AEGLs are defined as follows:


AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation or asymptomatic nonsensory effects. The effects are not disabling and are transient and reversible on cessation of exposure.

AEGL-2 is the airborne concentration of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape.

AEGL-3 is the airborne concentration of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death.

THE CHARGE TO THE COMMITTEE

The National Research Council convened the Committee on Acute Exposure Guideline Levels to review the AEGL documents approved by the NAC. The committee members were selected for their expertise in toxicology; medicine, including pharmacology; industrial hygiene; biostatistics; and risk assessment.



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Seventeenth Interim Report of the Committee on Acute Exposure Guideline Levels BACKGROUND In 1991, the U.S. Environmental Protection Agency (EPA) and the Agency for Toxic Substances and Disease Registry (ATSDR) asked the National Research Council to provide technical guidance for establishing community emergency exposure levels (CEELs) for extremely hazardous substances (EHSs) pursuant to the Superfund Amendments and Reauthorization Act of 1986. 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) on Acute Exposure Guideline Levels for Hazardous Substances. The NAC was established to identify, review, and interpret relevant toxicologic and other scientific data and to develop acute exposure guideline levels (AEGLs) for high-priority, acutely toxic chemicals. AEGLs developed by the NAC have a broad array of potential applications for federal, state, and local governments and for the private sector. AEGLs are needed for prevention of and emergency- response planning for potential releases of EHSs caused by accidents or terrorist activities. AEGLs are threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 min to 8 h. Three levels designated as AEGL-1, AEGL-2 and AEGL-3 are developed for each of five exposure periods (10 and 30 min, 1, 4, and 8 h) and are distinguished by degree of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation or asymptomatic nonsensory effects. The effects are not disabling and are transient and reversible on cessation of exposure. AEGL-2 is the airborne concentration of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death. THE CHARGE TO THE COMMITTEE The National Research Council convened the Committee on Acute Exposure Guideline Levels to review the AEGL documents approved by the NAC. The committee members were selected for their expertise in toxicology; medicine, including pharmacology; industrial hygiene; biostatistics; and risk assessment. 1

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The charge to the committee is to review the proposed AEGLs for scientific validity, completeness, internal consistency, and conformance to the 1993 National Research Council guidelines report; review the NAC’s research recommendations and—when appropriate—identify additional priorities for research to fill data gaps; and periodically review the recommended standard procedures for developing AEGLs. This interim report presents the committee’s conclusions and recommendations for improving the NAC’s AEGL documents for 17 chemicals: acetaldehyde, arsenic trioxide, benzene, 1,3-butadiene, butane, chloroacetaldehyde, chlorobenzene, hexane, jet propellant fuels 5 and 8, ketene, methylene chloride, oleum, propane, propionaldehyde, sulfuric acid, sulfur trioxide, and trichloroethylene. It also summarizes the committee’s conclusions and recommendations for improving the SOP). ACETALDEHYDE At its meeting held on October 27-29, 2009, the committee reviewed the AEGL technical support document (TSD) on acetaldehyde. A presentation on the TSD was made by Joanne Nijhof, of the Netherlands National Institute for Public Health and the Environment (RIVM). The following is excerpted from the executive summary of the TSD: Acetaldehyde is a colorless, highly volatile liquid at ambient temperature and pressure. . . . Available data for acetaldehyde included several recent human volunteer studies with very short exposure times, and two older volunteer studies with longer and more relevant exposure periods. Animal data were available for lethal and non-lethal endpoints in various species, and included also genotoxicity and carcinogenicity data. The AEGL-1 values are based on [a] human volunteer study . . . where workers experienced only mild respiratory irritation and no eye irritation following chamber exposure to acetaldehyde at a measured concentration of 134 ppm for 30 minutes. . . . The AEGL-2 values are based on histopathological changes observed in a study in rats. . . . The AEGL-3 values are based on 4-hour lethality data in rats. General Comments A revised document should be returned to the committee for review. The committee recommends that the acetaldehyde and propionaldehyde TSDs be combined into one document because the observed effects are generally similar at comparable concentrations. The acetaldehyde TSD should provide more information on the metabolism of acetaldehyde in humans and its polymorphism. The AEGL-3 values for acetaldehyde were adopted for propionaldehyde. 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. That the experiments were done via mouth breathing does not invalidate their findings and relevance: a sizable fraction of people are primarily mouth breathers, and some may have nasal obstructions (such as colds) that result in mouth breathing. In addition, under substantial stress or exercise, as may occur during an emergency alert and evacuation order, breathing shifts to a mixture of nose and mouth breathing. Finally, even regular nose breathers will inhale some fraction of their respirations via the mouth. In an emergency situation, exposures may occur via the nose, the mouth, or both. Those exposure routes therefore are relevant for assessing the uncertainty factor (UF) or intraspecies variability. A table should be developed to present the data from the human exposure experiments to facilitate review of exposure concentration and durations and the resulting health effects. It should be 2

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comparable with the tables developed for the lethal and nonlethal animal data. Such a table will also facilitate comparison with the proposed AEGL values. Comments on AEGL-1 to AEGL-3 Derivations AEGL-1: The committee agrees with an intraspecies UF of 3 but recommends that the interspecies UF be increased from 1 to 3. Stanek et al. (2001) mentions 25 ppm as a concentration above which vasodilation occurs. That must be considered an effect for AEGL-2 rather than AEGL-1. An AEGL-1 of 45 ppm is apparently too high. An intraspecies UF of 3 and an interspecies UF of 1 are insufficient. If the interspecies UF is increased to 3, that would lead to an AEGL-1 of 15 ppm for all exposure times, which accords better with the ACGIH TLV (Threshold Limit Value) for a 15-min short- term exposure limit (STEL) of 25 ppm. ACGIH adopted that TLV in 1993. It discarded the 8-h TWA and recommended a ceiling of 25 ppm (45 mg/m3). ACGIH also notes that susceptible humans may develop allergic sensitization even at the latter concentration. AEGL-2: The committee agrees with an intraspecies UF of 10 but recommends that the interspecies UF be 3. The reason is the potential effect of the acetaldehyde exposures on sensitive human subpopulations. 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]) to application to intraspecies UFs: from Section 2.5.3.4.1, p. 89, states that “if the toxicologic effects . . . are . . . less severe than those defined for the AEGL tier . . . an intraspecies UF less than 10-fold may be used” (emphasis added). In any case, 3, instead of 1, would have been a more reasonable choice for the UF less than 10. In the TSD, the AEGL-2 intraspecies UF of 10 is due to the existence of a susceptible human subpopulation and also represents the combined UF. A choice of an interspecies UF of 3 is also more reasonable in light of the derivation of the AEGL-3. AEGL-3: The committee agrees with an interspecies UF of 3 but considers the intraspecies UF of 3 to be too low. According to the TSD, a factor of 3 for intraspecies extrapolation should be sufficient to protect sensitive human subpopulations. A larger factor is “considered not necessary given the typical irritative aldehyde toxic action by acetaldehyde.” However, acetaldehyde has systemic effects in addition to local irritation, and these systemic effects are subject to polymorphic sensitivity in humans. The intraspecies UF should therefore be increased to 10. It is also more appropriate in light of the intraspecies UF of 10 in the AEGL2 derivation. Specific Comments Page 1, line 20: “Overall half-lives for acetaldehyde vary considerably” should be rewritten as “Overall environmental half-lives” or rather disappearance. In these documents, half-life usually refers to biologic half-life. Page 2: The whole section on “Human Toxicity Data” is too limited and based on obsolete data. The section should be rewritten after a new literature search and consultation with a clinical toxicologist. Page 3, line 35: “As a result of the polymorphism nearly half of the Japanese patients with asthma show bronchoconstriction after drinking alcohol, a phenomenon that is also known to occur in other Asian populations.” The statement should be revised for greater clarity; it should indicate that bronchoconstriction occurs after systemic exposure via ingestion, not inhalation. Page 4, line 13: Aerosol concentrations should be distinguished from vapor concentrations. The relevance of these data to the AEGL derivations should be given. Page 6, lines 11-13: “At concentrations of 0.2 to 0.7% in the blood marked increases 3

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in heart rate, ventilation and calculated respiratory dead space were observed, as was a decrease in alveolar CO2 levels.” It should be noted that these effects also occur after heavy drinking. Page 6, line 20: The authors state “No human studies on neurotoxicity were identified.” It is likely that at least one of the many neurotoxic effects of ethanol abuse can be ascribed to the acetaldehyde metabolite. Please search again. Page 6, lines 44 - 45: The statement “Overall IARC concluded that there is inadequate evidence in humans for the carcinogenicity of acetaldehyde (IARC 1999).” should be rechecked. It is the committee’s understanding that a more recent IARC monograph (vol. 96, still in process of publication) identified acetaldehyde as a “proven human carcinogen.” Page 7, line 48, through Page 8, line 3: The authors state “Finally the cat received 24500 mg/m3 (13720 ppm) for 15 minutes. This produced lacrymation, sneezing, marked salivation, agitation, convulsions, screaming, marked dyspnea, prostration, anesthetization and finally death.” Did the cats die during continued exposure or after discontinuation of exposure? Page 8, line 44: “The 4-hour LC50 was calculated to be 30.6 grams/m3 (17000 ppm).” Is 17,000 ppm vapor or aerosol? Page 9, line 6: “concentrations ranged from 14,000 to 57,000 mg/m3 (7840 to 31920 ppm).” Are the ppm values vapor or aerosol? Page 14, lines 13-20: It is hard to believe that this 1985 paper is the only one on supposed neurotoxicity. Moreover, Na-K-ATPase is not specific for brain tissue. It is the motor of the sodium pump that is present in all mammal cells. If the authors did not compare brain Na-K-ATPase with activity in other organs, this cannot be listed as neurotoxicity. A more profound literature search on acetaldehyde neurotoxicity is necessary. Page 17: In Section 3.6 on carcinogenicity, is it mere coincidence that mainly Dutch publications have been cited, such as Feron (1979) and Woutersen et al. (1986)? Page 17, lines 22-24: “An acute rat inhalation study by Stanek et al. (2001) showed vasodilatation already at concentrations of 25 ppm but the toxicological significance of this effect is doubtful (it may represent a physiological protective response).” Vasodilatation at over 25 ppm can hardly be seen as a “physiological protective response” (protective against what?) but rather should be considered an AEGL-1 effect. Page 18, lines 9-11: “Acetaldehyde is an intermediary in the normal catabolism of deoxyribose phosphate and various amino acids. A quantitatively much more important source of acetaldehyde in the body, however, is its formation through the action of alcohol dehydrogenase on ingested ethanol.” Ethanol formation in the human intestine by microorganisms (Blomstrand 1971) also leads to acetaldehyde formation. Page 18, line 24-26: “According to IPCS (1995) the conversion to acetic acid by aldehyde dehydrogenase constitutes the major biotransformation route for acetaldehyde. The acetate may enter into normal metabolism by the formation of acetyl-CoA, as is shown in the figure below.” The AldDH step is also the rate-limiting step in ethanol metabolism. 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) the dose delivered to the nasal tissue equals or exceeds the capacity of the enzyme. This capacity limitation they regard as the explanation of their previously observed higher efficiency of acetaldehyde uptake in rat nasal tissue at 10 ppm compared to 300 or 1500 ppm. Stanek and Morris (1999) also determined DNA-protein cross links in the nasal respiratory after a single exposure to 1500 ppm for 6 hours, a concentration clearly in excess of the aldehyde dehydrogenase metabolic capacity in this tissue, but failed to find an increase. Thus they could not reproduce the finding by Lam et al. (1986) who detected increased crosslink formation in the same tissue after exposure to 1000 ppm for 6 hours. The second to last sentence refers to an increase. What increase was looked for? Page 20, line 41: Does the fact that “no relevant data on species variability were identified” lead to the conclusion that no interspecies UFs have to be applied for this substance? 4

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Pages 23, line 34, through Page 24, line 7: After how many exposures was the degeneration of nasal epithelium observed by Appelman et al. (1982)? Comment References Appelman, L.M., R.A. Woutersen, and V.J. Feron. 1982. Inhalation toxicity of acetaldehyde in rats. I. Acute and subacute studies. Toxicology 23(4):293-307. Blomstrand, R. 1971. Observations of the formation of ethanol in the intestinal tract in man. Life Sci. 10(10):575-582. Feron, V.J. 1979. Effects of exposure to acetaldehyde in syrian hamsters simultaneously treated with benzo(a)pyrene or diethylinitrosamine. Prog. Exp. Tumor Res. 24:162-176. IARC (International Agency for Research on Cancer). 1999. Re-evaluation of Some Organic Chemicals, Hydrazine and Hydrogen Peroxide Part Two. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Vol. 71. Lyon France: IARC [online]. Available: http://monographs.iarc.fr/ENG/Monographs/vol71/index.php [accessed Jan. 19, 2010]. IPCS (International Programme on Chemical Safety). 1995. Acetaldehyde. Environmental Health Criteria 167. Geneva: World Health Organization [online]. Available: http://www.inchem.org/documents/ ehc/ehc/ehc167.htm [accessed Jan. 19, 2010]. Lam, C.W., M. Casanova, and H.D. Heck. 1986. Decreased extractability of DNA from proteins in the rat nasal mucosa after acetaldehyde exposure. Fundam. Appl. Toxicol. 6(3):541-550. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press. Stanek, J.J., and J.B. Morris. 1999. The effect of inhibition of aldehyde dehydrogenase on nasal uptake of inspired acetaldehyde. Toxicol. Sci. 49(2):225-231. Stanek, J.J., P.T. Symanowicz, J.E. Olsen, G. Gianutsos, and J.B. Morris. 2001. Sensory-nerve-mediated nasal vasodilatory response to inspired acetaldehyde and acetic acid vapors. Inhal. Toxicol. 13(9):807-822. Woutersen, R.A., L.M. Appelman, A. van Garderen-Hoetmer, and V.J. Feron. 1986. Inhalation toxicity of acetaldehyde in rats. III. Carcinogenicity study. Toxicology 41(2):213-231. ARSENIC TRIOXIDE At its meeting held on October 27-29, 2009, the committee reviewed the AEGL TSD on arsenic trioxide (As2O3/As4O6). A presentation on the TSD was made by Peter Bos, of RIVM. The following is excerpted from the executive summary of the TSD: Arsenic trioxide (As2O3/As4O6) is a white, odorless powder of low aqueous solubility. . . . AEGL- 1 values are not proposed, because there were no human or animal data available relating to AEGL-1 endpoints for arsenic trioxide. . . . No AEGL-2 effects were reported following acute inhalation exposure to arsenic trioxide. As an alternative, the AEGL-2 values are based on 1/3 of the AEGL-3 values. . . . The AEGL-3 values are based on lethality data in rats from a preliminary range-finding study of developmental toxicity. General Comments A revised document should be returned to the committee for review. Several suggestions are offered to support the re-evaluation of the interim AEGL values. First, it seems unusual that many important papers from groups with a long history of research on arsenic are not 5

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mentioned in the TSD, including those by Lauwerys (such as Buchet and Lauwerys [1998]), Aposhian (1989, 1997), Centeno et al. (2002), and the recent review article on arsenic neurotoxicity by Vahidnia, van der Voet, and de Wolff (2007). The committee recognizes that considerable effort was involved in identifying a number of key studies when the TSD was being prepared and that the document summarizes many data well. However, additional relevant papers have become available since the TSD was prepared, so it would be useful for the authors of the TSD to conduct a new search of the peer-reviewed literature for references that would strengthen the AEGL derivations, including key work discussed in the current arsenic toxicologic profile from the Agency for Toxic Substances and Disease Registry (ATSDR 2007), which updates the 2000 profile cited in the TSD. Second, the committee suggests that the authors consider human data for derivation of the AEGL- 3 and that relevance of toxicokinetic data be assessed with respect to study selection. For example, for arsenic, the rat is generally considered a poor model for humans (including permethylation and retention differences), and the rabbit is a better model; note that methylation has been considered to play a role in some detoxification processes because of the lower toxicity of metabolites, although more recently some have suggested that the converse might be indicated for specific end points. At higher exposure levels, some suggest that first-pass metabolism may be less of an issue. It has been reported that after exposures at high concentrations, much more arsenic trioxide is excreted compared with the typical high fraction of methylated compounds (Wang et al. 2004). That has suggested to some that oral data may provide useful context for higher inhalation exposure concentrations (which could be considered in this case as part of the AEGL-3 re-evaluation). In the same vein, intravenous data may offer useful insights for higher exposure concentrations. Some of the recent literature supports that concept. Thus, there are data, including some from studies published after the TSD was prepared, that suggest revisiting the AEGLs. The minimum lethal dose of arsenic trioxide has been reported to be 100-200 mg, and chelation treatment is recommended for arsenic exposure at over 50 mg (Dyro 2006a). Third, the authors should consider human data to support derivation of the AEGL-2. For example, the authors might use data on the therapeutic use of arsenic trioxide (notably for acute promyelocytic leukemia [APL]) in forming the AEGL-2 rather then using a default 1/3 adjustment from an AEGL-3 that was derived from a rat study. The medical literature suggests that the common therapeutic dose of 0.15 mg/kg-d is generally well tolerated; for example, some have reported that such toxic effects as leukocytosis and skin hyperpigmentation are minimal. It is important that the updated literature search and later discussion in the TSD consider information regarding the severity and reversibility of toxic effects. For example, in some instances, therapy involving arsenic trioxide is simply indicated as “safe,” or toxicity is identified as “minimal” without specific context regarding how serious or transient the toxic effects are. That applies notably to papers either that are publicly unavailable (and not yet acquired by the reviewer) or whose full form is in a foreign language. Examples of the first type include Ravandi et al. (2009), who indicate that therapy with arsenic trioxide is effective and safe; Pettersson et al. (2007), who state that “low doses of the drug can induce complete remission in patients with relapsed APL with minimal general toxicity”; and Douer and Tallman (2005), who state that “arsenic trioxide in the treatment of acute promyelocytic leukaemia is relatively safe with minimal side effects.” Examples of the second type include Xu et al. (2009) and Jiao et al. (2009). Some authors—such as George et al. (2004), Pettersson et al. (2007), and Sweeney et al. (in press)—generally refer to toxicity as minimal or mild and transient, whereas others provide further specific information regarding severity and reversibility, including Matthews et al. (2006), Fox et al. (2008), and Hu et al. (2009). Note that some others report serious toxicity, whose context (including dose regimen and patient status) should also be considered. The TSD authors should carefully evaluate those and other relevant studies in the new literature review. With respect to human variability (to support the intraspecies factor), treatment data exist for a range of ages, and this population subgroup that received therapeutic doses may be considered relatively sensitive given the subgroup’s health conditions. It should also be considered that the blood concentration associated with the therapeutic dose has been indicated to be around 100-250 μg/L (which is roughly 3-7 times the biologic exposure index of 35 μg of arsenic per liter [ACGIH 2008]), whereas the reported blood concentration associated with fatality is about 4-10 times that concentration, 1,000 μg/L. Those 6

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data suggest a context for the steepness of the dose-response curve in moving to the AEGL-3. In evaluating human data, the shorter biologic half-life in blood makes urinary concentrations more useful in a biomonitoring context: 24-h concentrations of 100-400 μg were reported in most of 41 patients who had arsenic-induced peripheral neuropathy (Dyro 2006b). (Note: to estimate a rough blood concentration from that information on urinary concentrations, a general daily adult urine output may be considered to be around 1 L or more, depending on various factors; the study information should be pursued to support a specific calculation.) With respect to human variability and concurrent exposures for purposes of deriving AEGLs, chronic alcohol consumption (a sensitive subgroup indicator) appears to contribute to the development and severity of peripheral neuropathy (Dyro 2006b). Fourth, the TSD authors should consider information on physiologically based pharmacokinetic (PBPK) models that have been developed for arsenic in a manner that was consistent with the general criteria identified in the PBPK modeling white paper prepared to support the AEGL derivation process (Dennison and Troxel [2006], pg. 6). Both the ATSDR (2007) toxicologic profile and the California EPA (CalEPA) technical support document for the arsenic reference exposure levels (OEHHA 2008) would serve as good overviews of the more recent literature on this topic (as well as the general toxicokinetics and mode of action). As summarized in those two documents, the PBPK suite includes the Mann model that evaluates inhalation of arsenic trioxide dust and addresses four chemical forms (two organic). The model has been validated with experimental data. That model was found to match observations well for 18 workers exposed at 10-1000 μg/m3. Such information can frame the consideration of human data for the AEGLs. As suggested by the information on blood concentrations illustrated above, linkage of insights from PBPK models with such human data would seem to support a more inclusive consideration of data currently available for derivation of AEGLs (in contrast with basing the values on rodent data, whose relevance has not been clearly demonstrated). Fifth, the TSD authors should further consider the relationship of the interim AEGLs to other established reference values and their bases, including the CalEPA acute and 8-h reference exposure levels, the National Institute for Occupational Safety and Health (NIOSH) concentration immediately dangerous to life or health (IDLH) (NIOSH 2005), and the U.S. Army Center for Health Promotion and Preventive Medicine (CHPPM) military exposure guideline (MEG) for arsenic (CHPPM 2004). For example, the CalEPA (OEHHA 2008) information may offer insights into derivation options for the AEGL-1. Finally, the cancer evaluation should be refined. The authors should clarify the EPA Integrated Risk Information System (IRIS) citations (the material should reflect current information rather than 1966 and 1997 references). The authors should consider related references (e.g., EPA 2005) regarding the draft slope factor, and they should also track the impending release of the updated arsenic assessment (see IRIS Track; the inorganic arsenic cancer assessment is expected to be finalized by March 2010 [EPA 2010]). EPA (2005) addresses increased susceptibility from early-life exposure to carcinogens that act via a mutagenic mode of action (MOA), emphasizing the period from birth (including lactational exposures) to adolescence (age, 16 years). In that guidance, EPA describes “focusing upon studies that define the potential duration and degree of increased susceptibility that may arise from childhood, defined as early- life (typically postnatal and juvenile animal) exposures.” That definition is qualified; EPA notes that “prenatal (in utero) exposures are not part of the current analysis. Studies that have postnatal exposure were included (without adjustment) even if they also involved prenatal exposure.” Thus, prenatal exposure may be reflected in the adjustment factors developed by EPA to address increased susceptibility. In any case, for carcinogens, it is useful to provide MOA context to address whether this further susceptibility could be an issue. Specific Comments Page vi, lines 11-15: (and parallel material in main text): “AEGL-1 values are not proposed, because there were no human or animal data available relating to AEGL-1 endpoints for arsenic trioxide. 7

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No AEGL-2 effects were reported following acute inhalation exposure to arsenic trioxide. As an alternative, the AEGL-2 values are based on 1/3 of the AEGL-3 values.” The authors should reconsider the availability of relevant data for AEGL-1 and AEGL-2 after pursuing an additional literature search (see General Comments, above). They should also reconsider the study selection for the AEGL-3, taking human data into account. Note that if animal data were used, a UF of 10 seems much too low for interspecies and intraspecies variabililty combined (particularly given that the end point currently used is not an irritant effect). The greater sensitivity of the human to the effects of arsenic can be supported by referring to the summary plots of no-observed-adverse-effect levels (NOAELs) and lowest observed- adverse-effects levels (LOAELs) in the ATSDR profile. Available data indicate that an interspecies UF of 10 and an intraspecies UF of 10 would be much more appropriate. Page 2, line 24, through Page 3, line 8: The literature cited in the “Oral Exposure” subsection of Human Toxicity Data (Section 2) is dated. More recent case reports are available; see, for example, Kim and Abel (2009) and Yilmaz et al. (2009). Page 3, line 21: What are “arsenic fumes”? Was this an As2O3 aerosol? It might have been arsine (AsH3), which has a toxicity profile different from that of As2O3. Page 3, lines 47-50: “Przygoda et al. (2001) report the existence of a group of people (Styrians) in a region of Austria in the 17th century that were ‘arsenic eaters.’ They consumed arsenic trioxide in amounts of 300-400 mg per dose at a regular basis (every 2-3 days) over lifetime, to improve their health. They seemed to have had no adverse health effects.” The TSD authors should check the current literature on the topic of tolerance, given the range of past and current (background) human exposures to arsenic. That would inform the adjustment for intraspecies (human) variability. Page 4, line 46: “No human experimental studies with arsenic trioxide were located.” Considerable literature exists on the experimental use of arsenic trioxide to treat patients for APL, which is now fairly routine; see, for example, Tallman and Altman (2009), Hu et al. (2009), and Ravandi et al. (2009). At least consider a reference to the section in which some earlier studies are cited (page 5, lines 36-42). In either case, it would be useful to provide more quantitative information from those studies. 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); see Holland et al. (1959) and others, including the technical summaries published by the California Office of Environmental Health Hazard Assessment (OEHHA 2008) and ATSDR (2007). A number of end points have been assessed as part of the safety and efficacy evaluations for this treatment (ranging from toothache to cardiac effects). Page 4, line 51: “Increased vasospastic reactivity in the fingers” is Raynaud’s phenomenon (which also occurs in several autoimmune diseases). The sentence should be phrased “. . . showed increased vasospastic reactivity in the fingers (Raynaud’s phenomenon).” Page 6, lines 4-6: The two major target organs for acute arsenic toxicity in humans are the gastrointestinal tract and the peripheral nervous system (PNS) in patients who survive. This brief text is insufficient to deal with this issue. Moreover, no references are given here. The mechanism of arsenic effects on the PNS is well known; see, for example, Vahidnia et al. (2007). PNS toxicity is also the major effect of chronic exposure to As2O3. Therefore, neurotoxicity of this substance deserves much more attention. For the older literature and the historical context, see De Wolff and Edelbroek (1994). Page 6, lines 28-36: Occupational exposure to atmospheric arsenic trioxide gives rise to increased incidences of lung cancer. This was found in studies among miners in China (Herz-Piciotto and Smith 1993), and among copper smelters in Montana (Lee-Feldstein 1986), Tacoma, WA (Pinto et al. 1977; Enterline and Marsh 1982; Enterline et al. 1987; Enterline et al. 1995) and Sweden (Järup et al. 1989; Sandström et al. 1989; Sandström and Wall 1993). Occupational exposure to other arsenic compounds (lead arsenate, calcium arsenate, copper acetoarsenite, and magnesium arsenate) in a 8

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pesticides factory also led to increased incidences of respiratory cancer (Ott et al. 1974). IARC (1987) concluded that there is sufficient evidence to classify the arsenic as a human carcinogen. Consider including more recent information, as suggested in the general comments; for example, see note regarding Lubin et al. (2000, 2008) citations. Also note (regarding route-specific context) that Smith et al. (2009) indicate increased lung-cancer risk regardless of whether arsenic is ingested or inhaled. Page 7, line 11, through Page 8, line 22: Section 3.1. The cat and mouse lethality data from early Flury experiments should be added to this section ahead of the rat data and other information that focuses on oral LD50s, and the summary in Section 3.7 should be revised accordingly. The cat data seem particularly useful because the 1-h LCLo of 100 mg/m3 for arsenic trichloride from Flury (1921), cited by NIOSH (1996), underlies the current NIOSH IDLH. Page 10, line 23: The neurotoxicity section says “no data.” It is unlikely that there are no data at all on neurotoxicity; a review of recent literature is recommended. Page 13, line 13, to Page 18, line 6: The discussion under “Metabolism and Disposition” is somewhat dated. The TSD authors should update this section with key new information from the recent literature; see summaries in ATSDR (2007) and CalEPA (OEHHA 2008) noted in the general comments above. Page 18, lines 7-18: As for the preceding comment, this section could benefit from a substantial update to reflect recent reviews, including Vahidnia et al. (2007), the summaries published by ATSDR (2007) and OEHHA (2008), and a number of recent publications in the primary literature. The updated information is expected to offer relevant insights for the AEGL derivations, for example, potentially to obviate a default 1/3 adjustment (for the AEGL-2) and inform better such factors as human variability (for example, with more recent information on polymorphisms). Page 21, line 20: The proposed AEGL-3 is 11 mg/m3, whereas the NIOSH recommended exposure limit-short term exposure limit (REL-STEL) (reported as arsenic) appears to be less than 0.1% of this level (Page 22). Can the enormous difference be justified? Page 22, Table 9: The authors should consider including the Occupational Safety and Health (OSHA) concentrations that trigger requirements for respiratory protection in the comparison of AEGLs with other reference levels. Note that for such comparisons, it might be helpful to indicate the AEGL concentrations as milligrams of arsenic per cubic meter of air (mg/m3), as was nicely presented for the occupational data summarized in Table 2). 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). Editorial Comments Page 13, line 13, to Page 18, line 6: We suggest retitling this discussion “Toxicokinetics” (which would be expected to address absorption, distribution, metabolism, and elimination—ADME) and organizing it into subsections that distinguish human from animal data (either within the common ADME components or overall). Page 18, line 25, to Page 19, line 7: Consider whether this information (updated) in Section 4.4.1, “Species Variability,” is more suited for the toxicokinetics discussion (see editorial comment above for Page 13) because it discusses data on metabolism. Page 19, line 13: “Sensibilisation” does not seem to be the correct term. Should the title read “Irritation and Sensitization?” Page 23: NIOSH is “. . . Institute for Occupational . . .,” and the IDLH is defined as “. . . life or health.”) Page 30, line 32: Marie Vahter’s name is misspelled as “Vather.” 9

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Comment References ACGIH (American Conference of Governmental Industrial Hygienists). 2008. TLVs and BEIs: Documentation of the Threshold Limit Values for Chemical Substances and Physical Agents, and Biological Exposure Indices. American Conference of Governmental Industrial Hygienists Cincinnati, OH. Aposhian, H.V. 1989. Biochemical toxicology of arsenic. Rev. Biochem. Toxicol. 10:265-299. Aposhian, H.V. 1997. Enzymatic methylation of arsenic species and other new approaches to arsenic toxicity. Annu. Rev. Pharmacol. Toxicol. 37:397-419. ATSDR (Agency for Toxic Substances and Disease Registry). 2007. Toxicological Profile for Arsenic. U.S. Department of Health and Human Services, Public Health Services, Agency for Toxic Substances and Disease Registry, Atlanta, GA [online]. Available: http://www.atsdr.cdc.gov/ toxprofiles/tp2.pdf [accessed Jan. 19, 2010]. Buchet, J.P., and R. Lauwerys. 1988. Role of thiols in the in-vitro methylation of inorganic arsenic by rat liver cytosol. Biochem. Pharmacol. 37(6):3149-3153. Centeno, J.A, F.G. Mullick, L. Martinez, N.P. Page, H. Gibb, D. Longfellow, C. Thompson, and E.R. Ladich. 2002. Pathology related to chronic arsenic exposure. Environ. Health Perspect. 110(Suppl. 5): 883-886. CHPPM (U.S. Army Center for Health Promotion and Preventive Medicine). 2004. Chemical Exposure Guidelines for Deployed Military Personnel. Technical Guide 230, January 2004 Addendum. U.S. Department of Defense, Army Center for Health Promotion and Preventive Medicine [online]. Available: http://chppm-www.apgea.army.mil/documents/TG/TECHGUID/TG230.pdf [accessed Jan. 26, 2010]. De Wolff, F.A., and P.M. Edelbroek. 1994. Neurotoxicity of arsenic and its compounds. Pp 283-291 in Handbook of Clinical Neurology, Vol. 64, P.J.Vinken, and G.W. Bruyn, eds. Amsterdam: Elsevier. Dennison, J.E., and C. Troxel. 2006. PBPK Modeling White Paper. Addressing the Use of PBPK Models to Support Derivation of Acute Exposure Guideline Levels (AEGL). November 16, 2006. Douer, D., and M.S. Tallman. 2005. Arsenic trioxide: New clinical experience with an old medication in hematologic malignancies. J. Clin. Oncol. 23(10):2396-2410. Dyro, F.M. 2006a. Arsenic: Treatment and medication. eMedicine, Dec. 6, 2006 [online]. Available: http://emedicine.medscape.com/article/1174215-treatment [accessed Jan. 19, 2010]. Dyro, F.M. 2006b. Arsenic: Differential Diagnosis. eMedicine, Dec. 6, 2006 [online]. Available: http://emedicine.medscape.com/article/1174215-diagnosis [accessed Jan. 19, 2010]. Enterline, P.E., and G.M. Marsh. 1982. Cancer among workers exposed to arsenic and other substances in a copper smelter. J. Am. Epidemiol. 116(6):895-911. Enterline, P.E., V.L. Henderson, and G.M. Marsh. 1987. Exposure to arsenic and respiratory cancer: A reanalysis. Am. J. Epidemiol. 125(6):929-938. Enterline, P.E., R. Day, and G.M. Marsh. 1995. Cancers related to exposure to arsenic at a copper smelter. Occup. Environ. Med. 52(1):28-32. EPA (U.S. Environmental Protection Agency). 2005. Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens. EPA/630/R-03/003F. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/ttn/ atw/childrens_supplement_final.pdf [accessed Jan. 19, 2010]. EPA (U.S. Environmental Protection Agency). 2010. IRISTrack Report for Arsenic, Inorganic Assessment. Integrated Risk Information System, U.S. Environmental Protection Agency [online]. Available: http://cfpub.epa.gov/ncea/iristrac/index.cfm [accessed Jan. 19, 2010]. Flury, F. 1921. Arsentrichlorid. In Uber Kampfgasvergiftungen. IX. Lokal reizende Arsenverbindungen. Zeit. Ges. Exp. Med. 13:527-528 (as cited in NIOSH 1996). 10

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Fox, E., B.I. Razzouk, B.C. Widemann, S. Xiao, M. O’Brien, W. Goodspeed, G.H. Reaman, S.M. Blaney, A.J. Murgo, F.M. Balis, and P.C. Adamson. 2008. Phase 1 trial and pharmacokinetic study of arsenic trioxide in children and adolescents with refractory or relapsed acute leukemia, including acute promyelocytic leukemia or lymphoma. Blood 111(2):566-573. George, B., V. Mathews, B. Poonkuzhali, R.V. Shaji, A. Srivastava, and M. Chandy. 2004. Treatment of children with newly diagnosed acute promyelocytic leukemia with arsenic trioxide: A single center experience. Leukemia 18(10):1587-1590. Hertz-Piciotto, I., and A. Smith. 1993. Observations on the dose-response curve for arsenic exposure and lung cancer. Scand. J. Work. Environ. Health 19(4):217-226. Holland, R.H., M.S. McCall, and H.C. Lanz. 1959. A Study of Inhaled Arsenic-74 in Man. Cancer Res 19: 1154-1156. Hu, J., Y.F. Liu, C.F. Wu, F. Xu, Z.X. Shen, Y.M. Zhu, J.M. Li, W. Tang, W.L. Zhao, W. Wu, H.P. Sun, Q.S. Chen, B. Chen, G.B. Zhou, A. Zelent, S. Waxman, Z.Y. Wang, S.J. Chen, and Z. Chen. 2009. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc. Natl. Acad. Sci USA 106(9):3342-3347. IARC (International Agency for Research on Cancer). 1987. Arsenic and arsenic compounds (Group 1). Pp. 100-105 in IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42, Supplement 7. Lyon: IARC [online]. Available: http://monographs.iarc.fr/ENG/Monographs/ suppl7/suppl7.pdf [accessed Jan 20, 2010]. Järup, L., G. Pershagen, and S. Wall. 1989. Cumulative arsenic exposure and lung cancer in smelter workers: A dose-response study. Am. J. Ind. Med. 15(1):31-41. Jiao, L., S.J. Wang, J.L. Zhuang, Y.Q. Zhao, D.B. Zhou, Y. Xu, B. Han, W. Zhang, M.H. Duan, N. Zou, T.N. Zhu, and T. Shen. 2009. Comparison of efficacy and adverse effects between arsenic trioxide and all-trans retinoic acid in patients with acute promyelocytic leukemia [in Chinese]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 31(5):555-558. Kim, L.H., and S.J. Abel. 2009. Survival after a massive overdose of arsenic trioxide. Crit. Care Resusc. 11(1):42-45. Lee-Feldstein, A. 1986. Cumulative exposure to arsenic and its relationship to respiratory cancer among copper smelter employees. J. Occup. Med. 28(4):296-302. Lubin, J.H., L.M. Pottern, B.J. Stone, and J.F. Fraumeni, Jr. 2000. Respiratory cancer in a cohort of copper smelter workers: Results from more than 50 years of follow-up. Am. J. Epidemiol. 151(6):554-565. Lubin, J.H., L.E. Moore, J.F. Fraumeni, Jr., and K.P. Cantor. 2008. Respiratory cancer and inhaled inorganic arsenic in copper smelters workers: A linear relationship with cumulative exposure that increases with concentration. Environ. Health Perspect. 116(12):1661-1665. Mathews, V., B. George, K.M. Lakshmi, A. Viswabandya, A. Bajel, P. Balasubramanian, R.V. Shaji, V.M. Srivastava, A. Srivastava, and M. Chandy. 2006. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: Durable remissions with minimal toxicity. Blood 107(7):2627-2632. NIOSH (National Institute for Occupational Safety and Health). 1996. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLH): Arsenic (inorganic compounds, as As). National Institute for Occupational Safety and Health [online]. Available: http://www.cdc.gov/ niosh/idlh/7440382.html [accessed Jan. 20, 2010]. NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket Guide to Chemical Hazards. Arsenic (Inorganic Compounds, as As). NIOSH Publication 2005-149. National Institute for Occupational Safety and Health [online]. Available: http://www.cdc.gov/niosh/npg/ npgd0038.html [accessed Jan. 20, 2010]. OEHHA (Office of Environmental Health Hazard Assessment). 2008. Inorganic arsenic reference exposure levels. Pp. 68-127 in Appendix D.1 Summaries Using this Version of the Hot Spots Risk Assessment Guidelines, Air Toxics Hot Spots Risk Assessment Guidelines, Technical 11

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justification for rejecting data is required; and Smyth et al. also did an oral LD50 study and reported that acetaldehyde was much less toxic than propionaldehyde—acetaldehyde LD50, 1,930 mg/kg, and propionaldehyde LD50, 1.4 mg/kg. The latter involved a different route of exposure and may indicate an important difference between chemicals and be a factor in assessing the degree of uncertainty in basing AEGL derivations on close analogy with acetaldehyde. The data from Salem and Cullumbine (1960) should also be discussed here because these aerosol exposures resulted in lethal effects at concentrations (1,207 ppm for 4-5 h) much lower than those reported by other studies that used vapor exposures, including that of Smyth et al. (1951). Page 10, lines 32-35: Sim and Pattle (1957) could be cited in support, given their (brief and sketchy) description of the effects of the sequence of acetaldehyde, propionaldehyde, butyraldehyde, and isobutyraldehyde. Page 12, lines 13-14: There is a terminologic issue here in how to describe “mild (sensory) irritation”—as an AEGL-1 end point or as a sub-AEGL-1 effect. Compare, for example, SOP Page 41, lines 9 and 27-28, and Page 42, line 12, with SOP Page 32, lines 11-15, and the diagram on Page 33. The “weight of the evidence” indicates that mild (sensory) irritation is considered a sub-AEGL-1 effect and is a toxicologic end point suitable for deriving AEGL-1 values. See specifically the first two paragraphs (Page 40) of SOP Section 2.2.2.1, and compare with the brief description in Sim and Pattle (1957). To reduce potential confusion, we suggest modifying the sentence to read “. . . severity of this effect is less than the AEGL-1 level, and. . . .” Page 12, lines 16-17: SOP Section 2.5.3.4.4 calls for a description of the mode of action, in this case direct irritation, and a discussion of why the response is unlikely to differ. The latter discussion is not present, but SOP calls for it (this is also true for the equivalent interspecies UF). It is particularly important for direct-acting irritants for which there is some question of whether there may be sensitive subpopulations; see SOP, Page 87, on respiratory irritants, such as sulfur dioxide, and appropriate UFs. Page 12, line 28: RD50 data are presented as relevant to the AEGL-1 on Page 12, lines 2-5, but no RD50 data are presented as relevant to the AEGL-2, for which it might be much more relevant. That is inconsistent. The data are described in the section “Animal Toxicity Data” and should be addressed here, even if they are not used for the derivation. Because the RD50 end point addresses a specific AEGL-2 effect, impairment of escape ability (SOP Section 2.2.2.2, Page 42), how the RD50 data on propionaldehyde (and on acetaldehyde) fit with the other AEGL-2-relevant data should be discussed here. If the data are not used for the AEGL-2 derivation, the specific reasons should be detailed. See the comment for Page 10, line 4, above. Page 13, line 7: The Driscoll range-finding data are referred to but without citation; see comment above for Page 7, lines 5-6, regarding the source of the data. Page 13, lines 8-11: No acute-exposure studies were deemed adequate for the derivation of AEGL-2s, apparently because no adverse effect was considered except histologically demonstrated damage to the nasal epithelium (see Page 17, lines 27-30). Although multiple-exposure studies have been used to derive AEGLs (SOP Section 2.5.3.2.9, Page 74), and end points that were neither incapacitating nor irreversible have been used (SOP Section 2.2.2.2.2, Page 43), more consideration should be given to the results of the other acute-exposure studies reviewed, if only to indicate the extent to which the results of the studies are (or are not) 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), but the fact that one-third of the proposed AEGL-3s are very similar to the derived AEGL-2s provides some additional confidence in the derivation. Additional support from among the propionaldehyde acute-exposure studies, perhaps the RD50 data and studies reported in the acetaldehyde TSD, should be identified. The reference to the TSD for acetaldehyde should be expanded to include citations, including the citation of the study referred to in that TSD and listing the Web site for the TSD for easy access (http://www.epa.gov/opptintr/aegl/pubs/acetaldehyde_%20interim_12_2008.v1_pdf.pdf). Page 14, lines 2-13: This discussion indicates that the Salem and Cullumbine (1960) data are of poor quality and are not used for the derivation of AEGL-3s. This is the only statement regarding the 44

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quality of these data, and some support for the assertion should be offered. Note that the data from this study reported in Table 4 of the TSD are consistent with the hypothesis that the toxicity of propionaldehyde is similar to but somewhat less than that of acetaldehyde. It may be worth comparing the data points from that study with the AEGL-3s: Salem and Cullumbine used 2,868 mg/m3 or 1,207 ppm and had 100% mortality in rabbits and mice after 4-5 h of exposure; the AEGL-3s are 1,100 ppm for 30 min and 530 ppm for 4 h. Although they are insufficient by themselves for deriving AEGL-3s, some explanation should be provided as to how they affect the derivation or why they do not. Page 14, lines 15-20: This paragraph lays out an appropriate approach to the derivation of the AEGL-3s. The argument needs to be strengthened; see the comment above for Pages 9-11, “Special Considerations,” on expanding the comparison with acetaldehyde. By elaborating on and providing support for the argument that acetaldehyde and propionaldehyde are comparable in toxicity, the assertion on line 19 can be justified. Note that data that do not support this argument and the uncertainties introduced by the data must be addressed. 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. Data on propionaldehyde were deemed unsuitable for deriving AEGL-3s, and these were set by assuming that the chemical is no more toxic than acetaldehyde and adopting its values. Page 32, Appendix D: Perceptible odor can be helpful in providing initial warning, and calculating a level of odor awareness (LOA) provides some quantitation for a typically qualitative measure. However, it is important to note that habituation to odors does occur and is sometimes complicated by temporary loss of the sense of smell. If an LOA is provided, a cautionary note should accompany it. Editorial Comments Cover Page: Consider using the structural formula to provide more information, especially inasmuch as Table 1 shows the chemical formula. Executive Summary: The general approach is good, but the detail in the derivation paragraphs, such as the time-scaling, could be reduced. Page 1, lines 3-4: Confirm that the phrasing “an addition of nucleophiles, an oxidation and a reduction” is the correct description of the chemical process. Page 1, Table 1: Consider including the saturated vapor concentration, which can be calculated if the vapor pressure is available; see Perez, C. and S. C. Soderholm (1991). Some Chemicals Requiring Special Consideration When Deciding Whether to Sample the Particle, Vapor, or Both Phases of an Atmosphere. Appl Occup Environ Hyg 6(10): 859-864. The Merck Index and Beratergremium für umweltrelevante Altstoffe are excellent references but are not widely accessible. If the information cited is also provided in other references, consider using something that is widely accessible, such as the on-line U.S. National Library of Medicine (NLM) databases or their EU equivalents. When citing these, indicate which database (e.g., ToxLine) and the date accessed. Odor: suffocating odor: Was any source identified for this description or any indication of relative concentration? Nothing is stated in the section on human toxicity, nor is it addressed in Appendix D. Explosive: Use the abbreviation UEL instead of the phrase “Upper explosion limit.” Conversion factors: When calculated by NTP with the standard industrial-hygiene value of 24.45 for RxT (the product of the gas constant in the ideal gas law and absolute temperature), slightly different values are obtained: 1 mg/m3 = 0.42 ppm and 1 ppm = 2.38 mg/m3. Consider recalculating these, at least in the cases in which it is easy to do, rather than accepting the value in a reference. Throughout 45

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the text, where values in ppm are provided in addition to values in mg/m3, if the values are provided by the author of the reference, consider recalculation to verify that the calculation was done correctly. Page 2, line 18: For chemicals with limited databases, such as this one, it may be helpful to the reader to include at the beginning a summary statement regarding whether and to what extent studies directly relevant to setting AEGL values were found, for example, studies that dealt with acute dose- effect relationships or repeated-dose studies that included first-day observations. The two summary slides from the presentation to the committee (“Toxicological Database for Propionaldehyde” Parts 1 and 2) provide a good basis for this kind of summary statement. The second and third paragraphs of the Executive Summary also do a good job of summarizing. Page 8, lines 7-8: The source of the genotoxicity data is listed as “as cited in BUA 1996”; were the primary references not available to cite directly? Page 8, line 48: Insert the concentration that guinea pigs were exposed to here, or state that it was the same as for mice and rabbits. Page 10, Table 4: In the first cell, check the spelling of “deference” and the concentration units. In the last row, express the concentrations in full rather than in scientific notation. Include the Appelman (1982) data. Page 12, line 38: Driscoll (1993) identifies the high concentration as 1,522 ppm; see page 14 of that report. Page 13, line 35: Insert the calculated ppm value for comparison. Indicate the extent of mortality in mice and rabbits (100%?) inasmuch as mortality in guinea pigs is listed as 15%. 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 . References used were Steinhagen and Barrow (1984), Gage (1970), and studies from Bushy Run Research Center, which may be the ones cited as Driscoll (1993). Page 17, lines 1 and 6: The current ACGIH TLVs are listed in The 2009 TLVs and BEIs booklet; the current documentation for these values is the Documentation of the Threshold Limit Values and Biological Exposure Indices, 7th edition, 2001, with supplements for 2002-2009. Page 19, line 4: What is the reference “GKNT”? If it stands for the Center for International Projects, that should be indicated by placing the letters in parentheses. Page 19, lines 19-20: This database is now available on line through the NIOSH databases Web site, http://www.cdc.gov/niosh/database.html. Page 19, line 21: The NLM toxicology databases are accessible through the Environmental Health and Toxicology web site, http://sis.nlm.nih.gov/enviro.html. The specific database used should be indicated. Appendix C Derivation Summary Tables AEGL-2: Exposure Route/Concentrations/Durations Block, and Effects Block: The high concentration is shown as 1,453 ppm, whereas the reference shows 1,533 ppm. Page 32, line 4: What is the meaning of “established at III”? Page 32, line 16: Citations for this and the other standards mentioned in this appendix would be appropriate, including Web sites if available. Page 32, line 21: “a Level 1 odor threshold” should be defined, or the specific reference or standard should be indicated; as phrased now, it is not clear whether it refers to the Japanese triangle method or the NVN2820 standard. 46

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Comment References ACHIH (American Conference of Governmental Industrial Hygienists) 2001. Documentation of the Threshold Limit Values and Biological Exposure Indices, 7th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. Alarie, Y. 1981. Dose-response analysis in animal studies: Prediction of human responses. Environ. Health Perspect. 42: 9-13. BUA (Beratergremium für umweltrelevante Altstoffe). 1996. Propionaldehyd (CAS-Nr. 123-38-6). BUA substance report No. 195. Stuttgart: S. Hirzel Verlag. Driscoll, C.D. 1993. Propionaldehyde: Combined Repeated-Exposure and Reproductive/Developmental Toxicity Study in CD Rats. Report No. 91U0086. Bushy Run Research Center, Union Carbide Chemicals and Plastics Company Inc., Export, PA. April 6, 1993 [online]. Available: oaspub.epa.gov/eims/eimscomm.getfile? p_download_id=471833 [accessed Jan. 26, 2010]. Egle, J.L. Jr. 1972. Effects of inhaled acetaldehyde and propionaldehyde on blood pressure and heart rate. Toxicol. Appl. Pharmacol. 23(1): 131-135 Gage J.C. 1970. The subacute inhalation toxicity of 109 industrial chemicals. Br. J. Ind. Med. 27(1): 1-18. Izmerov, N.F., I.V. Sanotsky, and K.K. Sidorov. 1982. Pp. 9-12, 102 in Toxicometric Parameters of Industrial Toxic Chemicals under Single Exposure. Center of International Projects, Soviet State Committee for Science & Technology (GKNT), Moscow. NRC (National Research Council). 2009. Acute Exposure Guidelines for Selected Airborne Contaminants, Volume 7. Washington, DC: The National Academies Press. Perez, C. and S. C. Soderholm. 1991. Some chemicals requiring special consideration when deciding whether to sample the particle, vapor, or both phases of an atmosphere. Appl Occup Environ Hyg 6(10): 859-864. Salem H., and H. Cullumbine. 1960. Inhalation toxicities of some aldehydes. Toxicol. Appl. Pharmacol. 2:183-187. Sim, V.M., and R.E. Pattle. 1957. Effect of possible smog irritants on human subjects. JAMA 165(15): 1908-1913. Smyth, H.F.,Jr., C.P. Carpenter, and C.S. Weil. 1951. Range-finding toxicity data: List IV. A.M.A.Arch. Ind. Hyg. Occup. Med. 4(2): 119-122. Steinhagen, W.H., and C.S. Barrow. 1984. Sensory irritation structure-activity study of inhaled aldehydes in B6C3F1 and Swiss-Webster mice. Toxicol. Appl. Pharmacol. 72(3): 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. The document was presented by Marcel van Raaij, of RIVM. The following is excerpted from the summary of the TSD: Sulfuric acid is one of the most produced chemicals in the world. It is a strong inorganic acid that is mainly used in the production of phosphate fertilizers. . . . The AEGL-1 values are based on respiratory irritation observed in many human volunteer studies at concentrations higher than 0.2 mg/m324. . . . Considering the database of more than 600 subjects tested for symptoms, the level of 0.2 mg/m3 is chosen as the point of departure for AEGL-1. . . . The AEGL-2 values are based on the absence of severe or disabling acute effects in the large number of experimental human volunteer studies as well as in the available occupational studies. . . . The AEGL-3 values are based on animal data, in absence of human lethality data. . . . The acute health effects of sulfuric acid (H2SO4), sulfur trioxide (SO3), and oleum are discussed in one TSD because sulfur trioxide and oleum will eventually be converted into sulfuric acid. Oleum (fuming sulfuric acid) is a mixture of sulfuric acid with up to 80% free sulfur trioxide. 47

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General Comments A revised document should be submitted to the committee for review. For AEGL-1, the concentration of sulfuric acid that can induce a change in specific airway resistance (SRaw) should be considered. Changes in SRaw are considered to be changes in airway function. Although a person may not feel the increase in SRaw, it is nonetheless a functional change that should not be ignored. It is not known whether changes in SRaw during an emergency could be augmented by other physiologic conditions and lead to incapacitation. The source of the comment that intra-individual variability of SRaw can be as high as 80% (Page 25, line 18 et seq.) is not clear. That also applies to the statement that a 20% change in forced expiratory volume in 1 second (FEV1) is needed to elicit discomfort. The TSD authors do note that effects on SRaw were observed mainly when people who had asthma withheld medication, but such people do not necessarily take medication all the time, so it is possible that exposure to acid could affect them during a release episode by altering SRaw to a point that causes discomfort. The authors need much stronger justification for not using SRaw as a relevant index for setting AEGL-1 that takes sensitive populations into account. Sulfuric acid has been shown to produce alterations in mucociliary clearance. The authors disregard that effect because the changes were not consistent. However, in both humans and animals, sulfuric acid has been shown to produce faster mucociliary clearance at low concentrations consistently and retardation of clearance at high concentrations. Retardation of mucus clearance could lead to mucus plugging in the small airways and to functional change in people who have lung diseases, such as asthma and chronic bronchitis. AEGL-2 was based on occupational exposure in a lead-acid battery plant (el Sadik et al.1972). The rationale of using the factory concentration is that the workers could tolerate sulfuric acid up to 31 mg/m3 without discomfort. It is not mentioned that the size of the acid droplets in the occupational- exposure scenario may not be the same as that from an acid release or especially from a sulfur trioxide release. It is well known that the toxicity of sulfuric acid varies with particle size. Acid particles in the battery plants tend to be larger than 1 μm, whereas those of acid formed from sulfur trioxide will be in the accumulation mode, below 1 μm. There is a potential for deeper lung penetration and greater effects with the latter than with the former. The derivation of AEGL-2 should consider the effects of sulfuric acid if particles were smaller, and the UF should be 10 here and for intersubject variability. Many of the animal toxicity studies were conducted with whole-body exposure conditions in which ammonia from feces and urine could neutralize the sulfuric acid aerosols. The toxicity studies should be divided into ones that used nose-only exposure and ones that used whole-body exposure. If toxicity was different between the two kinds of exposure, the lowest concentration that can produce an effect should be used. 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. Because there is no study that can be used as a guideline, the best approximation of such mixtures was probably the acidic atmospheres that occurred during severe air-pollution episodes, such as the 1952 London fog episode. During that episode, the increased mortality was associated with increased sulfuric acid concentrations. The AEGL should take that into consideration. The hydrogen ion concentration is thought to be responsible for the adverse effects of sulfuric acid. The AEGLs for sulfuric acid should be compared with those established for other acids, such as nitric acid and hydrochloric acid. Because sulfuric acid is present as droplets and could penetrate deeper into the lung than vapors of nitric acid and hydrochloric acids, it is believed that sulfuric acid could be the most toxic of these acids. The authors should search to see whether studies have compared the health effects of these acids and determine whether sulfuric acid is the most toxic of them. 48

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Specific Comments Page 3, lines 9-14: The case study (in Trinidad) by Daisly and Simmons (1999) is not relevant to the normal, airborne route of exposure to acid, so it should not be described in the document. Page 25, lines 23- 27: What is the source of the comment that intra-individual variability of SRaw can be as high as 80%? The same question applies to the statement that a 20% change in FEV1 is needed to elicit discomfort. The authors do note that effects on SRaw were observed mainly when people who had asthma withheld medication, but such people do not necessarily take medication all the time, so it is possible that exposure to acid could affect them during a release episode by altering SRaw to a point that causes discomfort. The authors need much stronger justification for not using SRaw as a relevant index for setting AEGL-1 that takes sensitive populations into account. Page 49, lines 27-45: Section 4.3.5. The effects of coexposure to other pollutants is not considered in setting the AEGLs, so this section should be deleted. Background concentrations are not complete. There are data for peak concentrations of acid in some areas, and these should be reported so that they can be compared with AEGL-1, which is fairly low. Page 50, lines 2-11: Section 5.1. It is stated that Avol et al. (1979) found no signs of irritation in people who had asthma at 0.1 mg/m3, but they did find that two of six showed increased airway resistance. Page 50, line 20: Section 5.3. The basis of AEGL-1 seems sound and consistent with previous irritant AEGLs. However, we suggest that AEGL-1 be reduced somewhat given that SRaw was altered in one-third of people who had asthma in the Avol et al. study noted above. SR cannot be ignored as a relevant end point for setting AEGL-1, at least in justifying its value. Page 52, Table 8: This table makes the issue confusing. 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. That does not support the idea that the effect of the acids is due solely to delivery of H+ to airway surfaces. One might think that only twice as many moles of HCl would be needed. So, that raises the question of what is actually responsible for the irritant effects of the compounds. Page 52, lines 27-30: The authors note that although effects were seen at 2 mg/m3 in people who had asthma, the symptoms were relieved by using medication. One cannot assume that during a release people who have asthma will be thinking about taking their medication. They may be incapacitated before that. Page 53, lines 28-50: Section 6.3. TLVs and occupational studies are not good PODs for AEGLs, because they generally are relevant only to healthy workers. This had been discussed at prior meetings of this committee. Thus, a no-effect level at a TLV or other occupational exposure should not be assumed to apply to sensitive populations. AEGL-2 needs to reconsidered because it is based on occupational exposure, and there needs to be strong justification for assuming that the proposed concentration will not affect people who have asthma, for example. Furthermore, the intraindividual variation should be 10, not 3, because there is wide variation in asthmatic response, and controlled studies do not examine people who have severe asthma. Page 53: Section 6.3, “Derivation of AEGL-2”: The AEG-2 value was based on results of El Sadik et al. (1972), but there is no mention that the acid droplets in the occupational-exposure scenario may not be the same size as those from an acid release or especially from a sulfur trioxide release. Acid particles in the battery plants tend to be larger than 1 μm, whereas those of acid formed from sulfur trioxide will be in the accumulation mode, below 1 μm. Thus, there is a potential for deeper lung penetration and for greater effects with the latter than with the former. Furthermore, the UF should be 10 here, as well for intersubject variability. Page 55, Table 10: Same comments as above for Table 8 on Page 52. Page 58, Table 15: The authors should explain the difference between AEGL-3 and ERPG-3. 49

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Editorial Comments Page 4, line 32, through Page 25, line 25: The organization of Section 2.2.2 needs to be simplified. Pages of tabular material are followed by detailed discussion of some studies. 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. Page 48, line 1: The name of Section 4.3.3, “Intraspecies Variability/Susceptible Populations,” does not seem to reflect its content. Perhaps it should be called “Effect of Ammonia on Acid Response.” Comment References Avol EL., M.P.Jones, R.M. Bailey, N.M.Chang, M.T.Kleinman, W.S.Linn, K.A.Bell, and J.D.Hackney. 1979. Controlled exposures of human volunteers to sulfate aerosols. Health effects and aerosol characterization. Am. Rev. Respir. Dis. 120(2): 319-27. Daisley, H., and V. Simmons. 1999. Forensic analysis of acute fatal poisonings in the southern districts of Trinidad. Vet. Hum. Toxicol. 41(1): 23-25 el-Sadik, Y.M., H.A. Osman, and R.M. el-Gazzar. 1972. Exposure to sulfuric acid in manufacture of storage batteries. JOM 14(3): 224-226. TRICHLOROETHYLENE At its meeting on October 27-29, 2009, the committee reviewed the TSD on trichloroethylene (TCE). The document was presented by Marcel van Raaij, of RIVM. The following is excerpted from the summary of the TSD: Trichloroethylene is a colorless, highly volatile liquid at ambient temperature and pressure. It has a sweet, chloroform-like odor. . . . Following exposure to trichloroethylene humans primarily experience central nervous system effects and irritation. At high concentrations cardiac arrhythmias have also occurred. . . . The AEGL-1 derivation is based on the exposure of volunteers to 300 ppm for 2 hours. . . . The AEGL-2 derivation is based on the same study. . . . At 1000 ppm for 2 hours the subjects reported light-headedness, dizziness, or lethargy. In addition reduced neurobehavioral performance was detected at this concentration, most importantly reduced performance in the pegboard test. Although significant in themselves, these effects are not escape-impairing. Thus the concentration of 1000 ppm for 2 hours is considered an adequate starting point for AEGL-2 effects in humans. . . . The AEGL-3 value is based on the acute mouse mortality study. . . . The NOEL from this study is 4600 ppm for 4 hours. General Comments A revised document should be submitted to the committee for review. The current document is 8 years old, and the authors need to update it and, if necessary, use new published data to derive AEGL values. 50

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The PODs for AEGL values need better justification. Specifically, the selection of the AEGL-1 POD needs to be transparent, given the human studies of TCE reported. 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. A POD of 300 ppm may be too high.  Although the effect is reported as marginal, an incidence of one of eight volunteers would still be the LOAEL, not NOAEL.  On the basis of Pages 3-7 of the TSD, the following data indicated lower LOAELs: 15 min: 95.8 ± 8.2 ppm (abnormal ECG with ventricular extrasystoles) (Konietzko et al. 1975c) 50-70 min: 100 ppm (reaction time) (Gamberale et al. 1976) 27 ppm (nose and throat mucous membrane irritation, drowsiness), 81 ppm (headache), 2 h: LOAEL of 201 ppm (dry throat) (Nomiyama and Nomiyama 1977) ≥2 h: 198-199 ppm (dry throat, throat irritation) (Stewart et al. 1970) 2.5 h: 75 ppm (suppression of sinus arrhythmia) ((Ettema and Zielhuis 1975; Ettema et al. 1975) 4h: 110 ppm (slight dizziness) (Salvini et al. 1971) ≤4h: 110-114 ppm (impaired Flanagan test) (Stewart et al. 1974)  A 3.5-h NOEL of 50 ± 11 ppm for auditory evoked brain potential was noted in a study by Winneke et al. (1976).  It was noted on Page 4 of the TSD that ATSDR used the POD of the LOAEL of 200 ppm from the Stewart et al. (1970) study which reported eye and throat irritation, fatigue, and drowsiness. Using ATSDR’s LOAEL of 200 ppm and its uncertainty of 3 (ATSDR 1997), a NOAEL would be 67 ppm. The 1977 study by Nomiyama and Nomiyama provides some support for that estimated NOAEL, specifically, headache at 81 ppm and drowsiness at 27 ppm (as reported in the TSD on page 3).  Alcohol-enhanced TCE effects are noted on Page 6 of the TSD for 2 h at 200 ppm (Windemuller and Ettema 1978). ATSDR also noted increase in heart and breathing rates at that concentration. Concomitant alcohol ingestion cannot be excluded from consideration for the general population. AEGL-2: POD at 2-h NOAEL of 1,000 ppm; PBPK @Ca = blood TCE at 18.3 mg/L. AEGL-2 is based on light-headedness, dizziness, or lethargy in combination with reduced performance in neurobehavioral tests of volunteers at 1,000 ppm for 2 h (Vernon and Ferguson 1969). These are noted as “sub” AEGL-2. A lower threshold can be found with similar end points. The following are summarized from Pages 3-7. LOAEL of 300 ppm (NOAEL, 100 ppm) (Howard Dolman and steadiness test) (Vernon 2h and Ferguson 1969) LOAEL of 150 ppm (suppressed sinus arrhythmia) (Ettema and Zielhuis 1975; Ettema et 2.5 h al. 1975) 4h LOAEL of 201 ppm (NOAEL, 81 ppm) (dizziness, anorexia, skin irritation), LOAEL of 100 ppm (slight dizziness) (Nomiyama and Nomiyama 1977) AEGL-3: POD at 4-h NOAEL of 4,600 ppm in mice.  The rationale for selecting the POD from the mouse study by Friberg et al. (1953) was that the benchmark-dose approach for obtaining the 95th lower bound of LC05 from the Adams et al. (1951) study 51

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results in too low an AEGL-3. It is noted that taking the NOAEL approach, the 4-h NOAEL would be 4,800 ppm from the Adams et al. study of rats—not very different from the chosen POD of 4,600 ppm in mice.  The proposed AEGL-3 for 30 min is 6,100 ppm. The AEGL-2 for 30 min is 620 ppm for 30 min and 960 ppm for 10 min. Please indicate whether it is a concern that the AEGL-3 is higher than the NIOSH IDLH of 1,000 ppm. The authors used an unpublished human PBPK model for TCE to derive AEGL-1 and AEGL-2 values. The human model was not validated against kinetic data. For the committee to accept PBPK- derived dosimetrics for time extrapolations, the models need to be published or undergo a documented peer review. The AEGL-2 human PBPK dosimetric was blood TCE. A primary metabolite, trichloroethanol (TCOH), is known to be responsible for CNS depression. 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. The authors need to use TCE and TCOH as dosimetrics for deriving AEGL-2 values. The AEGL-3 human PBPK model efforts were not useful and were abandoned in the TSD. That is probably because the dosimetric required in the PBPK model is TCOH, not TCE. The exposure conditions could result in saturation of the rate of formation of TCOH and lead to a different AEGL-3 profile for time extrapolations. Simulations should be redone to address that shortcoming. If there is still a problem (too high exposure to TCE), the PBPK modeling approach should not be used. Because in utero developmental effects—rat hydrocephalus at 500 ppm for 7 h/day in Belilies at al. (1980) and total litter loss at 100 ppm for 4 h/day in Healy et al. (1982; see Page 29 of the TSD)—can occur after a single day of maternal exposure during the window of vulnerability, the concerns regarding pregnant women should be adequately addressed. Other end points of oral exposures—such as decreased number of myelinated fibers in rat offspring hippocampus in Isaacson and Taylor (1989) and neurobehavioral effects in mice in Fredriksson et al. (1993; see page 30 of the TSD)—also point to the need to address those concerns. Specific Comments There should be results of a literature search conducted on carcinogenicity following SOP guidelines and criteria. Page 1, lines 21-22: What are the times associated with the use of TCE as an anesthetic? Page 8, Table 2: Data from Konietzko et al. (1975c) study (see I. AEGL-1 section above) should be included in the table, and please include time to effects. Comment References Adams, E.M., H.C. Spencer, V.K. Rowe, D.D. McCollister, and D.D. Irish. 1951 Vapor toxicity of trichloroethylene determined by experiments on laboratory animals. A.M.A. Arch. Ind. Hyg. Occup. Med. 4(5): 469-481. ATSDR (Agency of Toxic Substances and Disease Registry). 1997. Toxicological Profile for Trichloroethylene (Update). Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service, Agency of Toxic Substances and Disease Registry, Atlanta, GA. September 1997 [online]. Available: http://www.atsdr.cdc.gov/toxprofiles/tp19.pdf [accessed Jan. 26, 2010]. 52

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Beliles, R.P., D.J. Brusick, and J. Mecler. 1980. Teratogenic-Mutagenic Risk of Workplace Contaminants: Trichloroethylene, Perchloroethylene and Carbon Disulfide. NIOSH Contract Report No. 210-77-0047. NTIS PB-82 185-075. U.S. Department of Health and Welfare, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, Cinccinnatti, OH. Ettema, J.H., and R.L. Zielhuis. 1975. Effect of alcohol, carbon monoxide and trichloroethylene inhalation on mental capacity. Int. Arch. Occup. Environ. Health 35(2):117-132. Ettema, J.H., L. Kleerekoper, and J.W.C. Duba. 1975. Study of mental stresses during short-term exposure to trichloroethylene. Staub Reinhalt. Luft 35:409-410. Fredriksson, A., B.R. Danielsson, and P. Eriksson. 1993. Altered behavior in adult mice orally exposed to tri- and tetrachloroethylene as neonates. Toxicol. Lett. 66(1):13-19. Friberg, L., B. Kylin, and Å. Nyström. 1953. Toxicities of trichloroethylene and tetrachloroethylene and Fujiwara’s pyridine-alkali reaction. Acta Pharmacol. Toxicol. 9(4):303-312. Gamberale, F., G. Annwall, and B.A. Olson. 1976. Exposure to trichloroethylene. III. Psychological functions. Scand. J. Work Environ. Health 2(4):220-224. Healy, T.E., T.R. Poole, and A. Hopper. 1982. Rat fetal development and maternal exposure to trichloroethylene 100 ppm. Br. J. Anaesth. 54(3):337-341. Isaacson, L.G., and D.H. Taylor. 1989. Maternal exposure to 1,1,2-trichloroethylene affects the myelin in the hippocampal formation of the developing rat. Brain Res. 488(1-2):403-407. Konietzko, H., I. Elster, P. Schomann, and H. Weichardt. 1975c. Felduntersuchungen in Lösunsmittelnbetrieben. 4. Mitteilung: Herzrhythmustörungen durch Trichloräthylen. Zentralblatt für Arbeitsmedizin und Arbeitsschutz 5:139-141Nomiyama, K., Nomiyama, H. (1977) Dose- response relationship for trichloroethylene in man. International Archives of Occupational Environmental Health 39, 237-248. Nomiyama, K., and H. Nomiyama. 1977. Dose-response relationship for trichloroethylene in man. Int. Arch. Occup. Environ. Health 39(4):237-248. Salvini, M, S. Binaschi, and M. Riva. 1971. Evaluation of the psychophysiological functions of humans exposed to trichloroethylene. Br. J. Ind. Med. 28(3):293-295. Simon, T.W. 1997. Combining physiologically based pharmacokinetic modeling with Monte Carlo simulation to derive an acute inhalation guideline value for trichloroethylene. Regul. Toxicol. Pharmacol. 26(3): 257-270. Stewart, R.D., H.C. Dodd, H.H. Gay, and D.S. Erley. 1970. Experimental human exposure to trichloroethylene. Arch. Environ. Health 20(1):64-71. Stewart, R.D., C.L. Hake, A.J. Lebrun, J.H. Kalbfleisch, P.E. Newton, J.E. Peterson, H.H. Cohen, R. Struble, and K.A. Busch. 1974. Effects of trichloroethylene on behavioral performance capabilities. Pp. 96-129 in Behavioral Toxicology: Early Detection of Occupational Hazards, C. Xintaras, B.L. Johnson, and I. de Groot, eds. DHEW (NIOSH)74-126. U.S. Department of Health, Education and Welfare, Public Health Service, National Institute for Occupational Safety and Health, Washington, DC. Vernon, R.J., and R.K. Ferguson. 1969. Effects of trichloroethylene on visual motor performance. Arch. Environ. Health 18(6):894-900. Windemuller, F.J.B., and J.H. Ettema. 1978. Effect of combined exposure to trichloroethylene and alcohol on mental capacity. Int. Arch. Occup. Environ. Health 41(2):77-85. Winneke, G., U. Kramer, and J. Kastka. 1976. Zur Beeinflussung pschomotorischer Leistungen durch Alkohol und durch Verschiedene Lösungsmitteldämpfe. Pp. 99-110 in Adverse Effects of Environmental Chemicals and Psychotropic Drugs, Vol. 2. Neurophysiological and Behavioral Tests, M. Horvath, ed. Amsterdam: Elsevier. 53

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STANDING OPERATING PROCEDURES Before developing AEGLs for individual chemicals, the NAC developed the guidelines document Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Substances (referred to as SOP), which documents the procedures, methods, criteria, and other guidelines used by the NAC in the development of AEGLs. The information contained in SOP is based on guidance provided by the National Research Council in its guidelines report (NRC 1993). SOP was reviewed by the National Research Council AEGLs committee and published by the National Research Council (NRC 2001). In addition to reviewing AEGL documentation developed by the NAC, the National Research Council committee is charged to identify guidance issues from time to time that may require modification or further development on the basis of the toxicologic database for chemicals reviewed. 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”). 54