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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels Eleventh Interim Report of the Subcommittee 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 (NRC) 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, a subcommittee of the NRC Committee on Toxicology prepared a report titled Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances (NRC 1993). That report provides step-by-step guidance for the derivation of CEELs for EHSs. In 1995, EPA, several other federal and state agencies, and several private organizations convened an advisory committee—the National Advisory Committee on Acute Exposure Guideline Levels (AEGLs) for Hazardous Substances (referred to as the NAC)—to develop, review, and approve AEGLs (similar to CEELs) for up to 400 EHSs. 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 and emergency response planning for potential releases of EHSs, either from accidents or as a result of terrorist activities. THE CHARGE TO THE SUBCOMMITTEE The NRC convened the Subcommittee on Acute Exposure Guideline Levels to review the AEGL documents approved by the NAC. The subcommittee members were selected for their expertise in toxicology, pharmacology, medicine, industrial hygiene, biostatistics, risk assessment, and risk communication. The charge to the subcommittee is to (1) review AEGLs developed by the NAC for scientific validity, completeness, and conformance to the NRC (1993) guidelines report, (2) identify priorities for research to fill data gaps, and (3) identify guidance issues that may require modification or further development based on the toxicological database for the chemicals reviewed. This interim report presents the subcommittee’s comments concerning the NAC’s draft AEGL documents for 11 chemicals: chloromethyl methyl ether, jet-propulsion fuel 8, tetranitromethane, carbon monoxide, acetone cyanohydrin, monochloroacetic acid, phosphorus trichloride, phosphorus oxychloride, fluorine, cis-1, 2-dichloroethylene, trans-1, 2-dichloroethylene, and acrylic acid.
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels COMMENTS ON CHLOROMETHYL METHYL ETHER At its January 28–30, 2004, meeting, the subcommittee reviewed the AEGL document on chloromethyl methyl ether (CMME). The presentation was made by Sylvia Milanez of Oak Ridge National Laboratory. The subcommittee recommends a number of revisions. A revised draft would be reviewed by the subcommittee at its next meeting. Overall Comments The subcommittee recommends that comments on the AEGL values that would be derived on the basis of the toxicity for bis-chloromethyl ether (BCME) be added to the document. The AEGLs for BCME are expected to be similar to those calculated for CMME, after adjusting for the level of contamination. The explanations for not deriving an AEGL-1 need to be consistent throughout the document. Because CMME is classified as a human carcinogen, more detail on the cancer risk assessment and how it impacts on the AEGL values should be included in the main text of the document. The subcommittee recommends that data from single dose studies, including those involving BCME, be examined in more detail prior to AEGL-2. The use of single exposure studies might lead to AEGL-2 values exceeding those calculated on the basis of carcinogenicity. The sensitivity of the cancer risk assessment to different BCME contamination levels should also be examined. It should also be noted that the International Agency for Research on Cancer (IARC) classifies CMME as a “possible human carcinogen,” category 2B. General Comments The subcommittee was concerned about the use of a repeat exposure study (Drew et al. 1975) to derive the AEGL-2 values and suggests recalculating the AEGL-2 values using the single 7-hour exposure study in which exposures to CMME ranged from 0.7 to 9.5 ppm (Drew et al. 1975) and the single exposure studies with BCME. There was concern that the repeat exposure study might be inappropriate for the derivation of AEGL-2 values. At the concentration used to derive AEGL-2 values, 2 of 25 rats died, and death is an AEGL-3 effect. Three possible solutions were discussed: The easiest solution, but perhaps not the best, is to make a clear statement of why the repeat exposure study was used as the basis for AEGL-2 despite the occurrence of this AEGL-3 effect (e.g., by arguing that in the view of the author there is no good single exposure study, so, this multiple exposure study was chosen). Because of the repeated exposures, 2 of 25 rats died at 1 ppm, but that can be disregarded because a single exposure study acceptable for deriving AEGL-3 showed a LC01 (lethal concentration in one percent of the exposed animals) of 15 ppm (Drew et al. 1975). An alternative solution is to use the lung edema (lung-to-body weight change) from the single exposure study (Drew et al. 1975) to derive AEGL-2 values if that effect can be
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels considered serious and long lasting. (At 12.5 ppm, there was no mortality and no increase in lung-to-body weight ratios.) Use the Leong et al. (1975, 1981) studies that show that BCME at 10 ppb did not cause AEGL-2 effects in rats and mice. Uncertainty factors (UFs) of 3 were used to account for both species differences (interspecies) and intraspecies variability in the derivation of the AEGL-2 and AEGL-3 values. The reasons given for using those values need to be expanded and strengthened to justify deviating from the default value of 10. For AEGL-2, the reason given for using an interspecies UF of 3 is that “the key study is a repeat-exposure; CMME is a local-acting irritant (hydrolyzes in situ) and metabolism is unlikely to play a role in its toxicity” (page 24, lines 31–32). For AEGL-3, the reason given is that “rat and hamster yielded similar LC50 values in key study” (page 27, lines 30–31). Perhaps the intended meaning here is that the basis for choosing an interspecies UF of 3 was the same for both AEGL-2 and AEGL-3, but it does not come across that way. The reasons given should be consistent (if in fact the reasons are the same) and clearly stated. The basis for choosing the UF for AEGL-2 is especially troubling. That two animal species had similar LC50 values is not an adequate basis for determining that humans will respond in a similar manner to those two species. The reasons given for choosing these UFs needs to be expanded and strengthened to justify deviating from the default UF of 10. For intraspecies variability, the same reason is given for using a UF of 3 in AEGL-2 and in AEGL-3 values—response to an irritant gas hydrolyzed in situ “is not likely to vary greatly among humans” (page 28, line 23 and page 29, lines 1–2). The document has not established (with documentation) that response to an irritant gas is not likely to vary greatly among humans or that this is a sufficient basis for deviating from the default UF of 10. The reasons given for using these values need to be expanded and strengthened. The reasons and justifications presented for why AEGL-1 values were not calculated are inconsistent and thus confusing. The reason given in the text is that “there were no inhalation exposure studies with technical grade CMME that produced end points consistent with the definition of AEGL-1” (page 23). This description differs from the statements in the Executive Summary, in the summary table in the Executive Summary (page vii), and on page 29. That toxicity occurs below the odor threshold might be a reason to consider as well. A summary of the AEGLs values derived using cancer as a critical end point should be included in the text along with some analysis of the data. The text includes only a short statement that the calculation was done and that it did not impact the outcome. The risk level for each AEGL should be included along with a short discussion of its impact on the overall derivation of the AEGL values. The discussion of cancer assessment is not clearly presented. The design of the Kuschner study is unclear; the risk is incorrectly formatted as “10x −3”; the risk calculations are based on an assumption of 8% BCME, not on “pure” CMME, which needs to be explained better; it is unclear if the 6-fold modifier is appropriate for this substance; the NAC needs to determine if unit cancer risk is based on data from the 10-exposure study.
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels Specific Comments on Text Page vii, line 25. Two out of how many rats? Page vii, line 34. “AEGL-1 values were not derived” is repetitive (just stated above). Page viii, lines 9–10. Eliminate “of small populations in limited geographic areas.” Page 1, line 4. Add “which, however, is noted only at concentrations exceeding the lowest life-threatening concentrations” after “…with an irritating odor.” Page 1, lines 7–8. Add citation for the statement “Acute exposure can lead to delayed fatal pulmonary edema.” Page 1, lines 12–13. The t 1/2 for hydrolysis of CMME in water was extrapolated from that in aqueous isopropanol to be…? Page 7, line 22. Typo: “form” should be “from.” Page 12, lines 4–5. The exposure time for the Drew et al. (1975) study (30-day exposure study) is given in the original paper. The exposure time was 6-hours per day (see Table 5, page 65 of original Drew et al.  paper). Page 13, line 33. Give full terms instead of abbreviations. Page 14, Section 3.2.2. The second paragraph describes a study where mice were exposed for 6 hours to CMME at 14.6 to 100 ppm and none of the mice died within 14 days. Isn’t this a lethality study (even though it was negative)? Why not include this study in the lethality section? See page 10, lines 40–41: “Inhalation of 100 ppm CMME can apparently be tolerated (i.e., death does not occur) by animals for several hours (Hake and Rowe 1963).” Page 15, line 6. How much CMME? Page 15, line 16. How much CMME? Page 15, line 18. How much CMME? Page 15, line 30. Explain “demeanor.” Page 20, line 4. “CMME was degraded.” Within what time frame?
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels Page 20, lines 18–21. This does not appear to be fully plausible. Hence, it may be appropriate to write “It has been reported that the higher carcinogenicity” instead. Page 20, line 39. The text states that “the study by Drew et al. (1975) indicated that there is not a great deal of variability between species.” Drew et al. found that there was little difference in response and variability between two species—rats and hamsters. That is not sufficient evidence that humans will respond in the same way. See comment above. Page 21, Section 4.4.5, Neoplastic Potential of CMME by Other Routes of Exposure. In the past, we have typically not included data for routes of exposure other than inhalation. Is this meant to be supportive of the inhalation data? Page 23, lines 1–3. Perhaps a better argument would be “because concentrations leading to AEGL-1 effects are higher than those already causing AEGL-2 effects.” Page 23, lines 31–32. What was not specified? Page 25, line 23. Carcinogenicity calculations are in Appendix C, not B. Page 26, last paragraph. Shouldn’t this discussion mention that the median lifespan for animals exposed at both 6.9 and 9.5 ppm was 2 days? That is important. Page 28, lines 31–43. Summary explains more details than were explained in the preceding full text. Move part of the Summary to page 24 and 27. Page 30, Table 8, Extant Standards and Guidelines for CMME. Why not include and comment on the OSHA standard of 0.1 ppb for BCME? Page 30, lines 23–24. Should read “at concentrations below those leading to irritation and below the odor detection” Page C-2, Appendix C. Why was no UF used to account for intraspecies differences in the cancer risk assessment? Page E-2, Category Plot for CMME. The scale for this graph is incorrect. The axis values below 1 should not be zeros. COMMENTS ON JET-PROPULSION FUEL 8 At its January 28–30, 2004, meeting, the subcommittee reviewed the AEGL document on jet-propulsion fuel 8 (JP-8). The document was presented by Sylvia Talmage of Oak Ridge National Laboratory. The subcommittee recommends a number of revisions. The subcommittee will review the revised AEGLs draft at its next meeting.
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels Major Comments JP-8 is significantly different from JP-4. JP-8 is essentially kerosene with additives, whereas JP-4 is a mixture of gasoline (65%) and kerosene (35%) with additives. Much of the toxicological data presented in the document for JP-4 is associated with the light-end fraction (gasoline). That discussion should be eliminated. A better comparison is with kerosene or Jet A and Jet A-1 Because JP-8 has a very low vapor pressure, high concentrations are probably associated with aerosols. The toxicology of the lighter-end vapor components to the full-mixture aerosols makes exposure generation and evaluation of the data very complex. An interspecies uncertainty factor (UF) of 1 was used to derive the AEGL-2 values. The reason given for making that decision is that no adverse effects were observed and the exposures were repeated for up to 90 days (page 46, lines 22–23). This explanation is not convincing. Using an interspecies UF of 1 when relying on animal data is a major departure from past decisions as well as from the SOP. The subcommittee does not agree with the argument. If the NAC believes the UF of 1 is correct, the reasons for its use have to be clear and well stated. The current explanation is insufficient. The use of the Alarie’s 10-fold reduction factor is troubling. This procedure needs to be more fully described. As written, its basis is unclear. How well-established and accepted is it among members of the scientific community? Is it appropriate to use it here? Furthermore, there is no discussion of whether this one-time conversion step takes into account variability among species, such as effects on children and the elderly. The explanation for why no UFs were used is simplistic and unclear to anyone unfamiliar with this procedure. In the example used to support the AEGL-1 values derived from the Alarie 10-fold reduction factor, an interspecies UF of 1 was also used to derive AEGL-1. The justification given for that decision is that “no species differences were observed in multiple studies with rats and mice and the exposures were repeated” (page 45, lines 19–20). This is unconvincing. As stated above for AEGL-2, using an interspecies UF of 1 when relying on animal data is a major departure from past decisions as well as from the SOP. The subcommittee does not agree with the argument provided. If the NAC believes the UF of 1 is correct, the reasons for its use have to be clear and well stated. The current explanation is insufficient. Specific Comments Page 8, line 37. The subcommittee questions “18% aromatic hydrocarbons,” specifically calling out benzene, ethylbenzene, toluene, and xylenes. Although those components might be present, there are probably more higher-ringed components and if so, that should also be taken into consideration. The distillation fraction of JP-8 should minimize the presence of benzene and low-boiling aromatic hydrocarbons.
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels Page 12, line 1. Reference to Table 2 implies that the table includes information on health effects. (“Olsen compared the health of 18 Air Force personnel exposed to jet fuels with 18 non-exposed subjects.”) There are no health effects data in this table. Take out the reference or be more clear about why you are referring the reader to this table. Page 12, lines 9–10. It is stated here that subjects exposed to JP-8 had both “lower” and “higher” mean corpuscular hemoglobin. Which is correct? Page 12, lines 15–16. Enzymes were elevated in both groups but there are no differences? Either explain or eliminate as unnecessary information. Page 12, lines 26–30. This example—comparing effects following exposure to unleaded gasoline—is 60 years old (1943). Isn’t there a more recent study that could be used here? Pages 13–14, Table 2. Add data on benzene, xylene, toluene reported as part of these monitoring studies. Why are those data not included? This comment assumes that these substances make up a significant percentage of JP-8. Page 14, lines 16–21. Benzene is extremely difficult to separate from complex mixtures, especially in air, where the mixture is first trapped on an adsorptive media. This is especially true for short-term samples when quantities trapped are at or generally below the detection level. The appropriate analytical method is capillary gas chromatography with mass spectroscopy. Otherwise, identification by retention time leads to biased high results. Page 15, lines 15–26. Which hydrocarbons did Carlton and Smith (2000) monitor? Page 16, lines 1–3. Were any adverse health effects reported in Richie et al.? Page 16, lines 10–28. What is the toxicological significance of the effect of JP-8 on postural sway Smith et al. reported? Given that this is apparently not a manifestation of acute CNS effects (lines 23–25), does it reflect residual neurological dysfunction? How much time typically elapsed between the last JP-8 exposure and testing? Page 16, lines 17–18. Are benzene, toluene, and xylene exposures associated with postural sway? What about peripheral neuropathy? Page 16, line 30. It should probably be noted here (and in similar instances) that the findings of McInturf et al. (2001) were only reported in an abstract. Page 17, line 7. What is the origin of the 1,1,1-trichloroethane? Page 17, lines 13–14. Are these common dilutions? Is 1:75 toxic? Page 17, lines 23–24. Painters have a totally different exposure that includes ketones and aromatics, especially toluene and xylene.
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels Page 17, line 34. JP-4 is closer to aviation gasoline than JP-8. Page 17, Section 2.8, Carcinogenicity. What about data on the carcinogenicity of kerosene? ATSDR (1998) summarizes several studies that are not mentioned here. Why not include these as part of the document? Also, what about benzene, a component of JP-8? Should there be some mention of the carcinogenicity of JP-8’s components? Page 18, lines 21–22. How were aerosols measured? It seems strange to encounter aerosols during refueling. What is the aerosol generating process? Page 18, lines 26–27. This statement is incorrect. Statistically significant associations were found between exposures and increased postural sway, particularly for the components benzene, toluene, and xylene (page 16, lines 17–18). Page 19, line 13. It is surprising that the undiluted fuels did not produce eye irritation, because MacEwen and Vernot (1985) reported eye irritation in mice and rats exposed for 1 hour to JP-5 at 625 ppm. Other investigators have described eye irritation from exposure to JP-8. Page 19, lines 14–5. Were the undiluted fuels placed onto abraded or unabraded skin? Were occlusive patches applied? Page 20, lines 8–17. This is good methodology for testing and documenting the animal exposure. Page 22, Table 3. The NAC should list and describe the studies on JP-8 first and then include the other jet fuels. The focus of the document is on JP-8, so data on that fuel should be discussed first in the text and summarized first in the tables. It is distracting to have to go through all the data on JP-4 before getting to the data on JP-8. Page 27. Discussion on the toxicity of JP-4. Same comment as above. Start with studies on JP-8 and then include studies on other jet fuels. Page 28, lines 25–37. This paragraph describes effects of exposure to JP-5. Switch this paragraph with the next paragraph so that the two JP-5 studies are described together and the JP-8 studies are discussed as a group. Page 29, line 27. The upper bound of inhaled JP-8 concentration is said here to be 1,084 mg/m3, whereas in line 2 of the table on page 25 a value of 1,094 mg/m3 appears. Page 30, lines 32–33. It is believed that aerosols can pass through charcoal because they are trapped in the air stream and do not have enough Brownian motion to hit the charcoal. It is not clear how the authors distinguished between aerosol and vapor, although the conclusion that the vapor contained more light components than the vapor/aerosol is not remarkable—it is exactly what should happen. Page 31, lines 12–14. What is meant by “a saturation of the chemical in the nasal passages”?
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels Page 31, lines 15–18. n-nonane is C9. What are they trying to say? Page 31, lines 15–21. If the RD50 decreases with increasing lipophilicity of alkanes (e.g., for heptane to octane), how do this document’s authors account for the inability of nonane, decane, and undecane to reduce respiratory rate by 50%? Page 31, lines 22–34, and page 41, lines 3–5. Has the toxicological significance of the changes in protein expression been established, or even postulated? It would be a good idea to state that the observed changes are of uncertain significance, if that is the case. Page 32, line 3. Give a brief explanation of BALF fluid analysis. Page 34, lines 2–4. “The rats got stronger”? Pages 35–36, Section 3.4, Immunotoxicity. Was consideration given to using the immune studies to derive the AEGL values (Robledo and Whitten 1998 or Harris 2001)? Could those studies be used to derive AEGL values? Page 40, lines 12–13. This sentence does not make sense. It should be rewritten. Page 40, lines 15–16. Explain why “the male rat nephropathy and resulting kidney cancer associated with exposure to jet fuels is not relevant to humans.” It is not obvious to everyone. Page 41, lines 8–9. Although there are apparently no published absorption, distribution, metabolism, and excretion (ADME) studies of JP fuels, there have been investigations of the pharmacokinetics of combinations of ≥3 aromatics and/or long-chain aliphatics (Pedersen et al. 1984; Zahlsen et al. 1990, 1992; Lof et al. 1999). There have also been efforts to develop PBPK models for such mixtures (Tardif et al. 1997; Haddad et al. 2001). Page 41, line 37, and page 42, lines 8–10. It would be worth mentioning the “time-honored” mechanism of hydrocarbon-induced CNS depression. Because hydrocarbons are lipophilic, they partition into and accumulate in neuronal membranes and myelin. The more lipophilic the hydrocarbon is (i.e., the higher its neuronal tissue:blood partition coefficient), the more potent a CNS depressant it is. The mere presence of hydrocarbons has generally been thought to disrupt the ability of the neuron to propagate an action potential and repolarize. Recent research has revealed that hydrocarbons might act by more specific mechanisms and might affect specific neurotransmitters and membrane receptors. Hypotheses and pertinent experimental results have been published by a number of researchers, including Mihic et al. (1994), Engelke et al. (1996), Cruz et al. (1998), and Balster (1998). Page 42, lines 13–26. The potential relationship of the male-rat-specific nephropathy and nephrocarcinogenicity should be mentioned here.
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels Page 42, line 30. The phrase “to acute effects” should be inserted between “susceptibilities” and “usually.” Page 43, lines 2–3 The meaning of the following is unclear “N-acetyltransferase should have no effect on toxicity based on the composition of JP-8.” Page 43, lines 22–24. What is the basis for postulating that CNS depression is less dependent on duration of exposure than on exposure concentration? Duration of exposure is also a major determinant of dose until near steady-state or equilibrium is reached. Page 44, lines 12, 23. It is not clear how aerosols are generated during refueling. Unless that can be explained, the subcommittee recommends deleting references to refueling. It could be an issue during cold starts and also during foam replacement when saturated foam is pulled from the fuel tanks through small openings. Page 44, line 29. The phrase “exposures to JP-8 were generally low” is not germane to determining whether there are well-designed studies that identify reversible health problems relevant to AEGL-1 values. That phrase should be deleted from the text. Page 45, lines 8–11 The 10-fold reduction factor of Alarie et al. (1981) essentially includes a 3-fold factor for both intraspecies and interspecies variability. Page 46, lines 24–25 It would be worthwhile to point out that doses of volatile organic hydrocarbons (VOCs) absorbed systemically are considerably greater in mice and rats than in humans subjected to equivalent inhalation exposures. This is attributable to rodents’ relatively high respiratory rates, cardiac outputs, and blood:air partition coefficients. Therefore, no-effect levels for CNS depression in rodents are quite protective for humans. Page 47, line 7. Omit the word “lethal.” Page 47, lines 12–13, and 21–22: It is not accurate to state or imply that lethal JP-8 levels might be attained in confined spaces at high ambient temperatures. The highest vapor (only) concentration Wolfe et al. (1996) could generate was 3,700 mg/m3. A 4-hour exposure at that concentration was not lethal to any of a group of male rats. Most vapor levels measured within airplane fuel tanks are considerably lower. The only conceivable way a person might receive a lethal inhaled dose of JP-8 would be to inhale a very high aerosol concentration for a prolonged period of time. That is unlikely to occur, because the aerosol would be irritating to mucus membranes, and the individual would leave the situation. Page 50, lines 36–38. The statement that “exposure to higher concentrations of jet fuels occurred only when personnel were wearing respirators, thus negating the inhalation exposure route” is unclear and potentially misleading. The issue here is that workers wore respirators and thus adverse health effects were not observed; therefore, information on adverse health
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels effects could not be derived from these studies. The statement is repeated several times in the text, but the point is never made clearly. Summary The subcommittee believes that the JP-4 data do not add substantially to the scientific arguments made in the document for JP-8. AEGL-1 Values Because AEGLs generally have not been previously based on RD50 levels, the subcommittee recommends that the NAC provide a more detailed explanation of the rationale for deriving the AGEL-1 from the RD50. Specifically, the data from the Alarie study that support dividing the RD50 by a factor of 10 should be discussed. It could be explained that the Alarie data are consistent with human data showing no sensory irritation for other compounds, and a clear argument could be made for why no intraspecies UF was applied. AEGL-2 Values According to the NAC’s general rules for solvents, small animals receive a larger dose of direct acting compounds that affect the CNS than humans because of their more rapid respiration rate, which induces CNS effects. Therefore, the interspecies UF should be 2 or less; however, the intraspecies factor should be greater than 3. An interspecies UF of 1 was used to derive AEGL-2. The reason given for that decision was that no adverse effects were observed and the exposures were repeated for up to 90 days (page 46, lines 22–23). This explanation is not convincing. Using an interspecies UF of 1 when relying on animal data is a major departure from past decisions as well as from the SOP. The subcommittee does not agree with the argument. If the NAC believes the UF of 1 is correct, the reasons for its use have to be clear and well stated. The current explanation is insufficient. Further justification for the lack of time scaling for AEGL-2 (which is based on systemic toxicity) is also needed. The AEGL-2 seems a little high if based on escape impairment rather than irreversible health effects. The RD50 in mice was 2,876 mg/m3, and the recommended AEGL-2 was 1,100 mg/m3. This is a very high percentage of the RD50, and it might be satisfactory for healthy military personnel, but AEGLs apply to the general population. A suggested range is one-fourth or one-fifth of the RD50, unless there was data in asthmatics or more RD50-type data. Therefore, the subcommittee recommends a value in the range of 500 to 700 mg/m3 for AEGL-2.
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels AEGL-2 Values The subcommittee recommends that the NAC use a higher concentration. The concentration used actually fits the definition for AEGL-1. AEGL-3 Values Same as for AEGL-1 and -2. The AEGL-3 definition includes death; reversible effects and labored breathing do not fit the definition. COMMENTS ON ACRYLIC ACID At its January 28–30, 2004, meeting, the subcommittee reviewed the AEGL document on acrylic acid. The document was presented by Peter Griem of FOBIG GmbH, Germany. The subcommittee recommends the following revisions. A revised draft should be reviewed by the subcommittee at its next meeting. Major Comments The subcommittee is uncomfortable with NAC citing the Renshaw personal communication. It has not been provided to the subcommittee for review. What is the likely form of an exposure to the general public? It would seem that even if an aerosol was formed, it would quickly convert to vapor because of the relatively high vapor pressure of acrylic acid. Basing the AEGL on the aerosol requires further information. Is acrylic acid generally heated in the plant? It definitely is not when transported. The subcommittee postulates aerosols will rapidly evaporate to the vapor state. If that is the case, an AEGL derived on the basis of the vapor is more applicable. Provide current production quantities, number of U.S. and Western European facilities, and information on how it is handled and how it is transported. What is the opportunity for widespread release and dispersal of acrylic acid? Substantial difficulties remain with the draft technical support document. There remains considerable confusion between the notion of odor perception and irritation, and there is a failure to account rigorously for smoking (Cometto-Muiz and Cain 1982), gender (Cometto-Muniz and Noriega 1985), age (Stevens et al. 1982; Stevens and Cain 1986), and physiologic inurement on the part of the individuals surveyed. The NAC failed to distinguish between the objectionable odor associated with materials and frank irritation. It is important to take into account the quantitative differences between eye irritation threshold, nasal pungency, and odor threshold—the former of which often lays “orders of magnitude above odor thresholds” (Cometto-Muniz
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels and Cain 1995). Just as important, “persons with normal olfaction provide rather unreliable estimates of a nasal trigeminal threshold” and “it seemed necessary to rely strictly on the data from anosmic subjects who would have no distraction from accompanying odor” (Cometto-Muniz and Cain 1995). Controlled human quantitative structure-activity relationships exist for nasal pungency thresholds; those data are at present most robust for aliphatic alcohols, acetates, ketones, and carboxylic acids (e.g., Hau et al. 1999; Abraham et al. 1998; Cometto-Muniz and Cain 1993). In the present context, a current literature search might reveal similar studies with acrylates. Nevertheless, there seems to be no compelling reason that those data cannot be collected for a series of acrylates and acrylic acid before AEGLs for acrylic acid are adopted. What is the rodent RD50 for this material? How do AEGL values derived from the rodent RD50 compare with those derived from the anecdotal report of Renshaw (1988)? Specific Issues Page x, line 146. Does the statement here refer to ocular, mucous membrane, upper respiratory tract, or deep lung irritation or does it refer to all of those organ systems? Were the results obtained from controlled laboratory inhalation or instillation studies? Was the Renshaw (1988) report the result of simple anecdotal complaints? Describe here whether the people were male or female adults, smokers or nonsmokers, what the age range was, and whether the subjects were naïve or were workers accustomed to elevated concentrations of acrylic acid in workplace air. Were these complaints of irritation (what kind?) from people subjected to a single (preferably once-in-a-lifetime) exposure or from people who had a history of repeated occupational acrylic acid exposures (describe duration and range of concentrations routinely encountered) in workplace air? Page x, lines 147–152. The conclusions reached here relate to repeated inhalation exposure. Because AEGL values apply only to once-in-a-lifetime exposures, the many details from subchronic studies can only be used as supporting evidence, at best. As written, it is not clear whether these changes in rabbit, mouse, and nonhuman primates were seen after the first 6 hours (the first encounter) of exposure to airborne acrylic acid. Page x, line 165. Describe the cell system and whether clastogenicity was observed at only cytotoxic concentrations in vitro. Page x, line 171. As written, it is not clear why the irritation “threshold” is so broad (4.5–23 ppm) (Renshaw 1988). It appears that the acknowledged difficulties Renshaw had in reporting duration and concentration (page x, lines 174–175) render these data anecdotal and of such low confidence that they can only fill a supporting role in the present circumstance. Page xi, line 197 and page xiii, line 263. Specify species, gender, and age of the “monkeys” used in the Harkema (1997, 2001) assays. Page xi, lines 208–211. As presented, the text does not follow. The AEGL-2 is said (line 197) to be derived on the basis of the results of nonhuman primate inhalation studies conducted by
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels Harkema and associate, yet rats are mentioned at line 198 and the rat deposition data of Frederick et al. (1988) entered into identification of the interspecies UF? If the AEGL is based on the primate data, why is it necessary to re-work the rodent nasal end point here? Page xi, lines 216–217. Cite the specific SOP section that supports this conclusion. What data are available to justify the NAC generalization that “For local effects [what kind? Anesthesia?], the toxicokinetic differences [what kind? Rate of absorption?] between individuals are usually much smaller [by what factor?] when compared to systemic effects [like what?].” Delete the generalization unless specifics for acrylic acid can be included. Page xi, lines 217–220. How does the mode of action of acrylic acid differ so greatly among humans as to support a 3-fold reduction in the moderate primate olfactory changes after a continuous 3-hour inhalation exposure to acrylic acid? How were the changes “moderate”? Does NAC have data to support the development of nasal pathology in as little as 10 minutes after similar exposures? Page xi, line 220 and page xii, lines 221–223. What is the justification for applying an n derived from acrylic acid aerosol studies of mortality in rats to the vapor study results collected in primates by Harkema and coworkers? Page xiii, line 263. Why are the rat data referenced here when the AEGL-2, was derived from the Harkema nonhuman primate data (page ix, line 196)? Page 4, line 33. Why would whole-body exposure have a greater toxic effect than nose-only? Include the explanation presented at the last meeting. Page 22, lines 31–32. Is maternal toxicity different than other types of toxicity? The effects noted seem to be common to all species regardless of gender or pregnancy. If body-weight gain is the issue, emphasize that and state that eye and nose irritation also occurred. The reference to maternal toxicity was removed in Section 3.2.2. That is not the explanation provided in the comment-response section. Section 4.2. Is this the common mechanism of a simple irritant? Restated, is this a common irritant or is there another mechanism occurring? It is an unusual approach to calibrate a total hydrocarbon analyzer to an infrared instrument. Generally, standards are generated and the total hydrocarbon analyzer response is measured for a known concentration. The cited approach introduces potentially large sources of error. Pages 34–35, AEGL-2. It is stated that histopathological changes consistently are a more sensitive toxicological response than clinical signs of irritation. That statement is supported by comparison of these effects in three species (rabbits, rats, mice). If that is the case, are we being protective enough by using irritation response in humans as the basis for the AEGL-1? The monkey studies (Rohm and Haas 1995; Harkema et al. 1997; Harekma 2001) should be included in Table 10, in the Summary (Section 3.6, page 27), and in the mechanisms
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels discussion (Section 4.2, page 30). The human eye irritation data should be included in Figure 3. Summary AEGL-1 Values It should be emphasized that the present AEGL-1 value of 1.5 ppm is based on an evaluation of a wide range of occupational concentrations and provide a stronger rationale for the choice of 4.5 ppm as the starting point for the derivation of the AEGL-1. More details on the 11 human subjects should be given, including their inurement status. The RD50 should be included in the document, and its implications for the AEGL-1 should be considered. The AEGL-1 should also be discussed in relation to the TLV. AEGL-2 Values The monkey study, which represents the most suitable animal model for human risk assessment, seems most appropriate for the derivation of AEGL-2 values. Clearer explanations of the use of an interspecies UF of 1 and an intraspecies UF of 3 also need to be provided. The rodent data provide useful supporting information, leading to similar AEGL-2 values. Time-scaling should be based on default levels of n=1 and n=3, because n=1.8 is based on whole-body aerosol exposures. AEGL-3 Values The vapor data appears to be more relevant than the aerosol data. If the AEGL-3 is based on the vapor data (using the highest NOAEL from all of the available studies), the default time-scaling values of n=1 and 3 should be used. References Abraham, M.H., R.Kumarsingh, J.E.Cometto-Muniz, and W.S.Cain. 1998. An algorithm for nasal pungency thresholds in man. Arch. Toxicol. 72:227–232. Cometto-Muniz, J.E., and W.S.Cain. 1982. Perception of nasal pungency in smokers and nonsmokers. Physiol. Behav. 29:727–731. Cometto-Muniz, J.E., and W.S.Cain. 1993. Efficacy of volatile organic compounds in evoking nasal pungency and odor. Arch. Environ. Health 48(5):309–314. Cometto-Muniz, I.E., and W.S.Cain. 1995. Relative sensitivity of the ocular trigeminal, nasal trigeminal and olfactory systems to airborne chemicals. Chem. Sense 20(2):191–198.
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels Cometto-Muniz, J.E., and G.Noriega. 1985. Gender differences in the perception of pungency. Physiol. Behav. 34:385–389. Hau, K.M., D.W.Connell, and B.J.Richardson. 1999. Quantitative structure-activity relationships for nasal pungency thresholds of volatile organic chemicals. Toxicol. Sci. 47:93–98. Stevens, J.S., and W.S.Cain. 1986. Aging and the perception of nasal irritation. Physiol. Behav. 37:323–323–328. Stevens, J.C., A.Plantinga, and W.S.Cain. 1982. Reduction of odor and nasal pungency associated with aging. Neurobiol. Aging 3:125–132. COMMENTS ON CIS- AND TRANS-1,2-DICHLOROETHYLENE At its January 28–30, 2004, meeting, the subcommittee reviewed the AEGL document on cis-1,2-dichloroethylene (cis-1,2-DCE) and trans-1,2-dichoroethylene (trans-1,2-DCE). The document was presented by Cheryl Bast of Oak Ridge National Laboratory. The subcommittee recommends the following revisions. A revised draft should be reviewed by the subcommittee at its next meeting. General Comments AEGL-1 Values The use of a modifying factor (MF) of 2 should be justified on the basis of irritation-potency differences. AEGL-2 Values Narcosis is one mechanism for which there is documented evidence of species similarity in response and in critical lipid concentration necessary to produce such effects (see ecotoxicology literature by Lynn McCarty and others). The toxicodynamic component of the uncertainty factor (UF) should therefore be 1. It is acceptable to use a total factor of 10 to account for pharmacokinetic diferences within and between species. However, the authors should stay away from back-calculating the UF, even though some cross-checking is desirable. AEGL-3 Values The application of UF of 10 is acceptable for the above reasons. As pointed out earlier, back-calculating the UF is not recommended. Further, it may not be appropriate to say “twice as toxic” (Page 27, line 14), because the difference is likely the result of twice the exposure concentration needed to yield the same critical lipid concentration responsible for narcosis-mediated lethality.
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels Specific Comments Page 8, lines 22–24. Why not cite newer editions (12th or 13th) of the Merck Index? Page 10, lines 21 and 22. The two human guinea pigs inhaled 275–2,200 ppm, not mg/m3. Page 11, lines 5, 6, and 20. If six often rats succumb to cis-1,2-DCE at 13,500 ppm, wouldn’t the LC50 be lower than 13,700 ppm? Page 11, Table 3. Include a footnote that all of the deaths in exposed rats occurred during exposure to the chemical. Page 15, line 24, and page 26, line 5. The Freundt et al. (1977) study results are inconsistent with those of the GLP study by Kelly (1999). The morphological changes described by Freundt et al. are of very questionable toxicological significance and are probably undeserving of the extent of coverage they are given on page 15, line 24, and on page 16, line 5. It should be noted here that morphological changes were seen in just one of six rats (16%) exposed at 200 ppm versus five of 48 of the controls (10%). Page 16, line 43, and page 17, line 26. It would be worthwhile to summarize the subacute and subchronic oral toxicity studies by McCauley et al. (1995) and the NTP (2002) study. Extremely high daily doses of the cis and trans isomers had very little effect on rats or mice other than increased liver weights at the highest doses. These findings of an apparent lack of systemic toxicity support those of inhalation studies conducted by Kelly (1996) in rats. Page 19, lines 1–12. Can cis-1,2-DCE be characterized as a weak, moderate, or strong mutagen on the basis of these findings? Page 19, lines 32–34. It is stated that the 4-hour LC50 from Kelly (1999) for cis-1,2-DCE is 13,700 ppm and that the 4-hour lethality NOAEL is 12,100 ppm. Is the lethality dose-response curve actually that steep? Specify in the text that the NOAELs are for 4-hour exposures. Page 19, line 39. Substitute the word “potent” for “toxic.” Page 19, line 42, and page 20, lines 1–2. Loss of equilibrium in cats and mice is not equivalent to dizziness in humans. Intoxication/inebriation in humans would be closer. There is no physiological basis for the statement or assumption that “humans may exhibit equilibrium disturbances in a shorter period of time and at a lower concentration than the cat or mouse.” Four factors largely determine the extent of systemic absorption of 1,2-DCE (i.e., the absorbed dose and the target organ (brain) dose): (1) alveolar ventilation rate; (2) cardiac output and pulmonary blood flow rate; (3) blood:air partition coefficient; and (4) 1,2-DCE metabolism rate. The greater the systemic uptake of inhaled 1,2-DCE, the greater the central nervous system (CNS) depressant effect. All four factors are significantly greater for the mouse than for the human. Metabolism will reduce levels of
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels 1,2-DCE in the blood and tissues. 1,2-DCE nevertheless exhibits suicide enzyme inhibition (i.e., the more 1,2-DCE that is metabolized, the more that certain metabolites inhibit its biotransformation). There is a lack of applicable pharmacokinetic data and apparently no PBPK model with which to compare dosimetry in different species. Page 20, lines 11–14. The “pathological changes” reported by Freundt et al. (1977) should be discounted. The apparent morphological changes they described (e.g., hyperemia, alveolar septum distension, fibrous swelling, poorly maintained cardiac muscle striations), with the exception of fatty liver change, are vague, nonspecific, and of questionable toxicological significance. The findings of Kelly (1998, 1999)—no histological alterations in heart, liver, kidneys, and lungs after subchronic exposures—should be relied on instead. Page 20, lines 19–30 It is stated in lines 21 and 22 that 1,2-DCE has a “relatively high affinity for blood.” That statement is inaccurate. Its blood:air partition coefficients and those of other lipophilic chlorinated aliphatic hydrocarbons (halocarbons) are relatively low because of their limited solubility in blood (which is primarily aqueous). Relatively water-soluble hydrocarbons (e.g., ethanol, acetone) have much higher blood:air partition coefficients than 1,2-DCE. It is stated in lines 29 and 30 that “the cis isomer has higher PCs and therefore greater affinity or absorption in biological tissues.” That is only partially true. The higher blood:air partition coefficient of cis- 1,2-DCE (vs. trans) is a major factor in its more rapid and more extensive uptake into the systemic circulation and its greater narcotic potency. More pronounced metabolism of cis also favors its more extensive uptake. The two isomers have comparable oil:water partition coefficients and similar liver:blood and muscle:blood partition coefficients, so their uptake into those tissues from blood should be comparable. Page 20, lines 35–36. Barton et al. (1995), Lilly et al. (1998), and Hanioka et al. (1998) have published the results of more recent suicide enzyme inhibition studies of 1,2-DCE. Lilly et al. (1998) found the trans isomer to be more potent in that regard in male rats. However, Hanioka et al. (1998), observed that the isomers’ inhibitory effects were isozyme-specific and limited to male rats. Page 21, lines 11–13. Why is the Vmax for the cis isomer lower than that for the trans isomer if cis is more rapidly metabolized? Page 21, lines 22–32. It should be pointed out that CYP2E1-catalyzed oxidation of 1,2-DCE to an epoxide, 2,2-dichloroacetaldehyde, and 2,2-dichloroethanol represents metabolic activation. Each of these metabolites is cytotoxic. Collectively, they are likely responsible for the hepatic centrilobular fatty degeneration 1,2-DCE causes. The more rapid and extensive metabolism of the cis isomer and the more extensive production of dichloroethanol and its unstable predecessors from cis are consistent with this isomer’s greater ability to affect the liver (Kelly 1999). The delayed deaths in cats exposed during the investigation by Lehmann and Schmidt-Kehl (1936) might have been due to hepatotoxicity.
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels Page 21, lines 24–25. The paper by Gargas et al. (1990) should be cited here. 1,2-DCE-induced enzyme inhibition and resynthesis was also discussed for in a later publication by this research group (i.e., Lilly et al. 1998). Page 21, lines 34–39. The work of Eger et al. (2001) should be cited rather than that of Anon (1988a,b). Eger et al. (2001) found cis-1,2-DCE to be a more potent anesthetic in rats than trans-1,2-DCE. The authors felt that this supported the hypothesis that 1,2-DCE and other lipophilic anesthetics act by specific receptor interactions as opposed to simple partitioning into neuronal membrane lipids. Page 21, line 6. Insert the word “metabolic” at the end of this line. Page 21, line 24. This line should read “inhibition of the metabolism of other cytochrome P-450 substrates by 1,2-dichloroethylene.” Page 21, line 42. Substitute “cis” for “trans.” Page 22, line 2. Tables 7 and 8 should be Tables 8 and 9. Cite the source of these data (i.e., Lehman and Schmidt 1936). Page 22, line 6. Tables 4 and 6 should be Tables 5 and 7. Page 22, lines 11–13. The 6-hour LC50 of 21,723 ppm for trans-l,2-DCE might be of questionable accuracy. Was a complete translation of the report by Gradiski et al. (1978) available so that their study could be evaluated? Lehmann and Schmidt-Kehl (1936) found that all mice inhaling trans-1,2-DCE at 18,750 ppm for 102 minutes and at 20,000 ppm for 95 minutes died. It would be anticipated that the LC50s for mice would be significantly lower than those for rats. Mice will achieve higher blood and brain levels of 1,2-DCE because of their higher blood:air partition coefficient, pulmonary (blood) perfusion rate, alveolar ventilation rate, and 1,2-DCE metabolic rate. Page 22, lines 23–29. The results of Freundt and Macholz (1978) should be included here, namely that 1,2-DCE prolonged hexobarbital sleeping time and zoxazolamine paralysis time. These findings are a good illustration of the ability of 1,2-DCE to inhibit the P-450-catalyzed detoxification of certain chemicals. It might be worth noting that ethanol (and some other compounds) induce CYP2E1, an isozyme important in metabolic activation of 1,2-DCE and other halocarbons in humans. Page 22, lines 33–38. It does not appear that the use of Cn×t=k for time-scaling is warranted in deriving the 4- and 8-hour AEGL-2. One might anticipate that blood (and tissue) profiles for 1,2-DCE would resemble those of other well-metabolized halocarbons (that blood 1,2-DCE levels would increase rapidly upon initiation of an inhalation exposure and soon approach near-steady-state). Although no time-course data were located, Filser and
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels Bolt (1979) estimated that cis- and trans-1,2-DCE would attain near-steady-state within about 2 hours in rats inhaling 1,2-DCE at 100 ppm. If that is the case, blood levels and the extent of CNS depression would only increase modestly with increasing duration of exposure once near-steady-state was reached. This phenomenon is exhibited by trichloroethylene, another well-metabolized halocarbon (Bruckner et al. 2004). An apparent plateau for anesthetic effects is cited as the rationale for keeping the 10-, 30-, and 60-minute AEGL-2 values constant. 1,2-DCE is one of the few halocarbons that exhibits suicide enzyme inhibition. Metabolic inhibition would result in a decrease in the systemic uptake of inhaled 1,2-DCE. Lilly et al. (1998) observed virtually complete metabolic inhibition in rats inhaling trans-1,2-DCE at 10 ppm. Page 23, lines 34–37. It is not necessary to apply a modifying factor (MF) of 2 for cis-1,2-DCE. Its action as a mild direct irritant has nothing to do with its increased potency as a CNS depressant and hepatotoxicant. The same AEGL-1 values should apply to the cis and trans isomers. Page 25, lines 1–3. Hurtt et al. (1993) do not state when narcosis first became evident in the pregnant rats during the 6-hour exposures. It seems quite likely that narcosis ensued within the first hour or two and became somewhat more pronounced during the last 4 hours (judging from the aforementioned pharmacokinetic calculations of Filser and Bolt ). Have any data been published showing the magnitude of CNS depression as a function of time of inhalation of a fixed vapor concentration? The classic interspecies uncertainty factor (UF) of 10 is assumed to consist of two UFs of 3, one for potential pharmacokinetic differences and one for potential pharmacodynamic differences. As described earlier in this critique, mice and rats should absorb more 1,2-DCE and attain higher brain levels than humans after equivalent inhalation exposures. The toxicodynamic component of the UF should be close to 1, because there is well-documented evidence (see ecotoxicology literature by Lynn McCarty and others) of interspecies similarities in the critical lipid (brain) concentration of a halocarbon required to produce a given level of narcosis. It would nevertheless be prudent to retain a total interspecies UF of 3, as was done for the derivation of AEGL-2 and AEGL-3 values. It will also be prudent to retain the intraspecies factor of 3 for AEGL-2 and AEGL-3 derivations. A number of investigations have shown that there is relatively little intraspecies variability in the vapor concentration of anesthetics required to produce anesthesia, despite differences in age, body weight, and other factors. (Gregory et al. 1969; Stevens et al. 1975; de long and Eger 1975). Page 26, lines 16–18. It should be stated here that Kelly saw no histopathological changes in the liver, heart, kidneys, or lungs of any rats in the LC50 study. Page 26, line 19. Give the 20,000–114,000-mg/m3 values in ppm so that they can be more readily compared with the values in lines 1–3.
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Eleventh Interim Report of the Subcommittee on Acute Exposure Guideline Levels Page 26, line 28. Insert “up to 4,000 ppm” between “to” and “trans” at the end of the line. Page 26, lines 33 and 34. A vapor level of trans-1,2-DCE at 12,300 ppm—a NOEL for death of rats—was chosen as the basis for 4- and 8-hour AEGL-3 values. The cat (Table 7) is apparently more susceptible to 1,2-DCE lethality, although the cats were exposed to cis-1,2-DCE. Justify the use of the rat data. References Barton, H.A., J.R.Creech, C.S.Godin, G.M.Randall, and C.S.Seckel. 1995. Chloroethylene mixtures: Pharmacokinetic modeling and in vitro metabolism of vinyl chloride, trichloroethylene, and trans-1,2-dichloroethylene in rat. Toxicol. Appl. Pharmacol. 130:237–247. Bruckner, J.V., D.A.Keys, and J.W.Fisher. 2004. The acute exposure guideline level (AEGL) program: Applications of physiologically based pharmacokinetic modeling. J. Toxicol. Environ. Health, Part A, 67:621–634. de long, R.H., and E.I.Eger. 1975. AD50 and AD95 values of common inhalation anesthetics in man. Anesthesiology 42:384–389. Eger, E.I., M.J.Halsey, D.D.Koblin, M.J.Laster, P.Ionescu, K.Konigsberger, R.Fan, B.V. Nguyen, and T.Hudlicky. 2001. The convulsant and anesthetic properties of cis-trans isomers of 1,2-dichlorohexafluorocyclobutane and 1,2-dichloroethylene. Anesth. Analg. 93:922–927. Gregory, G.A., E.I.Eger, and E.S.Munson. 1969. The relationship between age and halothane requirement in man. Anesthesiology 30:488–491. Hanioka, N., H.Jinno, T.Nishimura, and M.Ando. 1998. Changes in hepatic cytochrome P450 enzymes by cis- and trans-1,2-dichloroethylenes in rat. Xenobiotica 28:41–51. Lilly, P.D., J.R.Thorton-Manning, M.L.Gargas, H.J.Clewell, and M.E.Andersen. 1998. Kinetic characterization of CYP2E1 inhibition in vivo and in vitro by the chloroethylenes. Arch. Toxicol. 72:609–621. McCauley, P.T., M.Robinson, F.B.Daniel, and G.R.Olson. 1995. The effects of subacute and subchronic oral exposure to cis-1,2-dichloroethylene in Sprague-Dawley rats. Drug Chem. Toxicol. 18:171–184. Stevens, W.C. et al. 1975. Minimum alveolar concentrations (MAC) of isoflurane with and without nitrous oxide in patients of various ages. Anesthesiology 42:197–200.
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Representative terms from entire chapter: