Nineteenth 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 (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, the NRC published Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances in 1993. Subsequently, Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Substances was published in 2001; it provided updated procedures, methods, and other guidelines used by the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances for assessing acute adverse health effects.

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 NAC have a broad array of potential applications for federal, state, and local governments and for the private sector. AEGLs are needed for emergency-response planning for potential releases of EHSs, from accidents or terrorist activities.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). AEGL-2 and AEGL-3, and AEGL-1 values as appropriate, will be developed for each of five exposure periods (10 and 30 min and 1 h, 4 h, and 8 h) and will be distinguished by varying degrees of severity of toxic effects. It is believed that the recommended exposure levels are applicable to the general population, including infants and children and other individuals who may be susceptible. The three AEGLs have been 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 certain asymptomatic nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.

AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) 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 (expressed as ppm or mg/m3) 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 NRC convened the Committee on Acute Exposure Guideline Levels to review the AEGL documents approved by NAC. The committee members were selected for their expertise in toxicology; medicine, including pharmacology and pathology; industrial hygiene; biostatistics; and risk assessment.



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Nineteenth 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 (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, the NRC published Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances in 1993. Subsequently, Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Substances was published in 2001; it provided updated procedures, methods, and other guidelines used by the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances for assessing acute adverse health effects. 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 NAC have a broad array of potential applications for federal, state, and local governments and for the private sector. AEGLs are needed for emergency-response planning for potential releases of EHSs, from accidents or terrorist activities. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). AEGL-2 and AEGL-3, and AEGL-1 values as appropriate, will be developed for each of five exposure periods (10 and 30 min and 1 h, 4 h, and 8 h) and will be distinguished by varying degrees of severity of toxic effects. It is believed that the recommended exposure levels are applicable to the general population, including infants and children and other individuals who may be susceptible. The three AEGLs have been 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 certain asymptomatic nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) 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 (expressed as ppm or mg/m3) 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 NRC convened the Committee on Acute Exposure Guideline Levels to review the AEGL documents approved by NAC. The committee members were selected for their expertise in toxicology; medicine, including pharmacology and pathology; industrial hygiene; biostatistics; and risk assessment. 1

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The charge to the committee is to (1) review the proposed AEGLs for scientific validity, completeness, internal consistency, and conformance to the NRC (1993) guidelines report; (2) review NAC’s research recommendations and—when appropriate—identify additional priorities for research to fill data gaps; and (3) periodically review the recommended standing operating procedures (SOP) for developing AEGLs. This interim report presents the committee’s conclusions and recommendations for improving NAC’s AEGL documents for 25 chemicals: allyl alcohol, bis-chloromethyl ether, chloromethyl methyl ether, bromine pentafluoride, bromine trifluoride, chlorine pentafluoride, carbon tetrachloride, chloroform, chlorosilanes (26 selected compounds), epichlorohydrin, formaldehyde, hydrogen bromide, hydrogen iodide, methyl bromide, methyl chloride, nitric acid, nitric oxide, nitrogen dioxide, nitrogen tetroxide, piperidine, titanium tetrachloride, toluene, trimethylbenzenes (1,2,4-; 1,2,5-; and 1,3,5-TMB), vinyl acetate monomer, and vinyl chloride. ACRYLONITRILE At its meeting held on October 26-29, 2010, the committee reviewed the technical support document (TSD) on acrylonitrile. A presentation on the TSD was made by Julie Klotzbach, of Syracuse Research Corporation. The following is excerpted from the Executive Summary of the TSD: Nonlethal effects of occupational exposure to AN [acrylonitrile] include headache, nasal and ocular irritation, thoracic discomfort, nervousness and irritability.… The AEGL-1 values were based on the absence of effects in informed human volunteer subjects (6 males) exposed for 8 hours to 4.6 ppm AN.… The 4.6 ppm value is recommended for all AEGL-1 exposure durations…. The AEGL-2 values were based upon slight transient effects in rats exposed to 305 ppm AN for 2 hours…. The AEGL-3 values were derived using 30-minute, 1-, 4-, and 8-hour BMCL05 estimates of lethality threshold. A revised document should be submitted to the committee for review. AEGL-Specific Comments AEGL-1 The point of departure (POD) of 4.6 ppm is based on six male toxicologist volunteers 28-45 years old (Jakubowski et al. 1987). A discussion of the uncertainty associated with the POD should include considerations that the focus of this study was for the metabolism of arylonitrile, not for identifying acute toxicity. In additions, considerations should be given for the small sample size, and the male-only adult subjects. Further, it should be clearly stated that the volunteers for the Jakubowski study were toxicologists working in the same laboratory as the lead authors, as this raises some ethical concerns. Yet, as three studies (Jakubowski, Sakurai, and personal communication) indicate a similar effect level, the committee agrees with the choice of the Jakubowski study for AEGL-1. Also see “Other Comments” regarding Page 10, lines 10-12, regarding the use of “personal communication” as supporting evidence. Page 6, lines 13-14 (also see page 15, line 11): Since children may be more sensitive to acute inhalation, given that the POD was based on observations in adult males, the decision for not applying an intraspecies uncertainty factor (UF) to derive the AEGL-1 needs either adequate justification or revision. Page 30, Section 5.1, Human Data Relevant to AEGL-1 (also see page 31, lines 14-35): The TSD also enlisted three ranges of occupational exposure as lending support to the proposed AEGL-1 2

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when an intraspecies UF of 3 is applied. In addition to the inconsistent use of applying the intraspecies UF here but not for the 4.6 ppm above, additional considerations are needed for each listed range of exposure. They are listed below:  Page 30, line 42; page 31, line 2 and lines 18-21: A range of 12 to 15 ppm for ocular irritation and headache in occupational exposure was based on a NAC/AEGL personal communication. However, no data are presented in TSD for review. These data need to be presented in the AN document.  Page 10, lines 30-42: A range of 10 to 20 ppm was based on a survey of workers reported by Sakurai et al. (1978). The associated toxicities were headache, nervousness, fatigue, nausea, and insomnia. Some of these effects may have exceeded the threshold end points for AEGL-1 and warrant additional modification factor. Moreover, the TSD attributed additional confidence to this range of exposure because the surveyed workers were routinely exposed to AN. However, it is not clear that these end points would occur only after repeated exposure, especially since the overall data presented throughout the TSD indicate that these effects are not all cumulative with repeated exposure. In fact, the rationale for holding one AEGL-1 value for all durations of exposure would indicate otherwise.  Page 5, lines 5-12 (also see page 30, lines 35-37): A third range of 16 to 100 ppm for 20-45 min was taken from Wilson et al. (1948). The associated toxicities were dull headache, fullness in the chest, mucous membrane irritation (including eyes, nose, and throat), apprehension, and nervous irritability (Wilson et al. 1948). It is not clear how all of these effects are determined to be “of greater sensitivity than the AEGL-1 definition,” as stated on page 30, line 37, especially when compared with the end point for AEGL-2, for example, slight ocular and nasal irritation. Please provide additional discussion. AEGL-2 Page 32, lines 25-26: The POD was based on a 2-h exposure to 305 ppm that resulted in slight transient ocular and nasal irritations in rats. These end points are apparently milder than the effects reported in the three sets of concentration ranges used to support the derivation of AEGL-1. The end points of developmental toxicity and other systemic effects (e.g., hearing loss) as detailed in Other Comments should be considered together with irritation end points selected for use for the proposed AEGL-2. Page 32, line 27-28: The meaning is unclear for the following sentence: “The interspecies uncertainty factor was limited to 3 because a non-human primate is considered a more relevant model than rodents.” This statement should be supported with an explicit comparison between the two species and the humans. Then, data from the former should be used if it is a preferred species for the POD. The choice of associated interspecies UF should subsequently be justified. Due to the lack of quality data from humans, the POD for AEGL-2 is based on data from laboratory animals. However, some of the human data may be useful for bounding the AEGL-2. For example, 60 of the 144 acute AN poisoning cases evaluated by Chen et al. (1999) were reported on page 10, line 19-21, to be from exposures at 18-258 ppm. A closer look at the publication indicates that 18 of the 60 cases were exposed at 40-79 mg/m3 (18-36 ppm) for 1.0-3.5 h. Apparently, dizziness, headache, feebleness, and chest tightness occurred in all these cases because these effects occurred in 100% of the 144 cases. Because these effects may impair the ability to escape, it would be prudent to consider setting the AEGL-2 values below 18 ppm for up to 4 h unless adequate justification can be given to exclude this set of data. 3

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AEGL-3 Page 33, lines 37-38: The interspecies UF was limited to 3 on the basis of the physiologically based pharmacokinetic (PBPK) model results. However, the description for the rationale is incomplete, and supporting data are insufficiently presented for its justification. Specifically, the rationale for the interspecies UF of 3 was only given later in the AEGL-3 table on page 59, that is, it “is considered sufficient to account for possible toxicodynamic/metabolism differences.” This explanation should also be included here for the sake of completing the concept. Also, the Kedderis and Fennel 1996 paper from a CIIT publication was cited on page 33, line 41, as demonstrating similar AN and cyanoethylene oxide (CEO) dose metrics between humans and rats. However, no data were presented in the TSD for review, and the CIIT report cannot be located for review. More important, the results of PBPK modeling by Sweeney et al. (2003) showed that instead of being similar, the brain AN and brain and blood CEO concentrations estimated in humans are generally 2-fold higher than in rats exposed to AN at 2 ppm for 8 h or at continuous 0.4 ppm exposure. Thus, if the intraspecies UF of 3 is needed for pharmacodynamic variability, an additional 2-fold uncertainty would be needed to account for the pharmacokinetic differences. Other Comments The list of end points for the study by Wilson et al. (1948) was given multiple times throughout the TSD; however, they were not consistently described. Please harmonize the descriptions of this study. Tables 2 to 7: Orient entries in these tables consistently regarding the dose or exposure level (e.g., low to high) and exposure duration (e.g., short to long). Tables 8 to 10: Add exposure regimen “6 h/day, GD 6-15” to the table title or the footnote study citation. Page 6, line 15, to page 7, line 2: reference citations are needed for the data mentioned Page 10, lines 10-12 (also see page 31, lines 1-2 and lines 18-21): The TSD states “Additional reports (see NAC/AEGL, personal communication) affirmed that occupational exposure at 12 to 15 ppm resulted in ocular irritation and headache.” The use of personal communication for supporting information on human exposure is not appropriate for this document unless the information is publically available. Section 2.3.2 of the Standing Operating Procedures (SOP) requires that data on humans must be “used from sources that are publicly available,” (page 53). Is this study now published? If the study has since been published, please provide the appropriate reference. If it has not been published, the public source for the “NAC/AEGL personal communication” should be given in Section 9 references. Page 10, Section 2.2, Nonlethal Toxicity: This section includes a mixture of different study types, some of which do not necessarily reflect toxicity. The first paragraph (lines 2-4) on odor threshold should not be in this section. Perhaps, it could be in the Introduction. The case studies and perhaps the epidemiologic studies also should not be in a section called Nonlethal Toxicity. Page 11, Section 2.3, Developmental and Reproductive Effects: The presentation of developmental toxicity should be expanded to ensure adequate protection against potential developmental effects from acute maternal exposure. For example, fetal morphogenic alterations from a single maternal oral exposure during the gestation period were reported at 100 mg/kg in rats (Saillenfait and Sabate 2000) and at 80-120 mg/kg in hamsters through the intraperitoneal (i.p.) route (Willhite et al. 1981). These data are not included in the TSD arguably because they are not from inhalation studies. However, the Willhite et al. (1981) and its companion study by the same researchers were included in the propionitrile TSD. A more fundamental concern is that developmental effects are pertinent systemic toxicity end points, especially since Section 4.1(pages 27-28) indicated that AN is rapidly absorbed after inhalation exposure, with 52% to 91.5% retention. Please provide additional discussion on these issues. Although maternal toxicity was present at fetal toxicity levels, distinction should be made between the reversibility of many observed maternal effects versus irreversibility of the developmental 4

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effects. This distinction could affect the selection of the POD for AEGL-2 and AEGL-3. For example, in the Murray et al. (1978) study, maternal weight gain (Table 8, page 22) apparently recovered after its severe suppression of the initial two to three 6-h/day exposures (that is, 95% lower weight gain at 40 ppm and weight loss at 80 ppm). However, fetal effects of omphalocele, anterior displaced ovaries, missing vertibrae, short tail, and trunk (Table 10; page 23) are permanent. Page 12, lines 11-13: “The authors, however, reported that the overall results supported the null hypothesis for AN-induced effects in people living in the vicinity of the AN factory.” What was the actual null hypothesis? Please include this information in the TSD. Page 15, Section 3.1, Acute Lethality and Page 20, Section 3.2, Nonlethal Toxicity: Present the animal toxicity data for lethality and nonlethal toxicity in consistent order according to the test species (e.g., monkey, rat, dog, and guinea pig,) Page 15, lines 10-12: “Although no exposure terms are available and information is limited, children appeared to be more susceptible than adults in the same exposure conditions.” If no exposure terms are available, how can one conclude that children are more susceptible than adults for the same exposure? Please provide an explanation for this statement. Page 25, line 44: “Group II” was not specified before this point. Could this be the “Group II” mentioned in line 35? Page 26, lines 17-18: The sentence “The increased mortality for the 20-ppm females was the result of early sacrifice due to benign mammary gland tumors” needs clarification. Did the benign tumors cause them to be moribund and warranted early sacrifice? Page 26, lines 28- 29: “The frequency of Zymbal’s gland tumors was significantly increased (11/100; p < 0.05) in both male and female animals….” The sentence needs revision. The incidence of 11/100 given here is only for the males, not for “both males and females” Page 26, lines 34-36: “Based on astrocytoma incidence data reported by Quast et al. (1980), Felter and Dollarhide (1997) reported a calculated risk range from 8.5 × 10-6 to 1.1 × 10-5, which yields a 1 × 10-4 risk specific concentration of 9 μg/m3 from chronic exposure based upon the LED10.” This sentence is awkward. What exposure scenario is associated with the given risk? Also, the expression “1 × 10-4 risk specific concentration of 9 ug/m3” is awkward. Is this “unit risk”? If so, please use the term “unit risk”. Page 27, Table 12, Tumor Type and Incidence Data for Rats Exposed to AN Vapor: Do these data include interim sacrifices? This should be clarified so that they would not be directly used for modeling cancer potency. Page 27, lines 2-24, Section 3.6: Reference citations are needed for the data mentioned Page 27, lines 22-23: “Results of inhalation exposure cancer bioassays have shown that AN is carcinogenic in rat brain, spinal cord, Zymbal’s gland, tongue, and nonglandular stomach.” There is no report of stomach tumors in this TSD. Either delete stomach from this list or add the appropriate data into the document. Page 29, lines 21-22: Enhanced noise-induced hearing loss was reported by Fechter et al. (2003) in rats shortly after receiving 40 mg/kg through subcutaneous injection. This systemic effect was apparently not tested through the inhalation route but should be discussed in the document and included as an end point for AEGL considerations. Page 27, lines 30-31: “AN with absorption exhibiting a biphasic pattern….”: What is a biphasic pattern? Page 31, lines 21-22: “It is reasonable to assume that for AEGL-1 severity effects, individual variability in the response to AN would vary no more than 3-fold….” Is it reasonable to assume based on the occupational exposure studies? If so, provide a sentence to state this explicitly with appropriate justification. Page 31, lines 25-27: “This is slightly lower than the no effect level of 10 ppm noted in the occupational exposure findings but is appropriate for the general public who may not be accustomed to acrylonitrile exposure as would workers.” On the basis of what scientific evidence? The appropriate reference(s) should be provided. If references are unavailable this sentence should be deleted. 5

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Page 32, Section 6.3, Derivation of AEGL-2 Values: The section indicates that the AEGL-2 value is based on rats (line 25), but then goes on to state, “interspecies uncertainty factor was limited to 3 because a non-human primate is considered a more relevant model than rodents, dogs or cats” (lines 27- 29). This is somewhat confusing. Perhaps the justification for the UF of 3 needs to be rephrased to state “because variation was observed across the different species.” Otherwise, if primate data are more relevant, why is rodent data being used to derive the AEGL-2 values? Page 32, lines 29- 31: “The intraspecies uncertainty factor was limited to 3 because the effects associated with acute irritation effects of AN are not likely to vary greatly among individuals and because metabolism may be of limited relevance regarding such effects.” What is the basis for the comment on line 31 that metabolism may be of limited relevance. Page 34, Section 8.2, Comparisons with other Standards and Guidelines: A discussion for the 2-fold difference between the proposed 30-min AEGL-3 (180 ppm) and the corresponding immediately dangerous to life or health (IDLH) (85 ppm) is needed. Comment References Chen, Y., C. Chen, S. Jin, and L. Zhou. 1999. The diagnosis and treatment of acute acrylonitrile poisoning: A clinical study of 144 cases. J. Occup. Health 41(3):172-176. Fechter, L.D., S.F. Klis, N.A. Shirwany, T.G. Moore, and D.B. Rao. 2003. Acrylonitrile produces transient cochlear function loss and potentiates permanent noise-induced hearing loss. Toxicol. Sci. 75(1):117-123. Felter, S.P., and J.S. Dollarhide. 1997. Acrylonitrile: A reevaluation of the database to support an inhalation cancer risk assessment. Regul. Toxicol. Pharmacol. 26(3):281-287. Jakubowski, M., I. Linhart, G. Pielas, and J. Kopecky. 1987. 2-Cyanoethylmercapturic acid (CEMA) in the urine as a possible indicator of exposure to acrylonitrile. Br. J. Ind. Med. 44(12):834-840. Kedderis, G.L., and T.R. Fennell. 1996. Development of a Physiologically Based Description of Acrylonitrile Dosimetry. CIIT Activities 16(1), January 1996. Murray, F.J., K.D. Nitschke, J.A. John, A.A. Crawford, J.S. Murray, L.W. Rampy, and B.A. Schwetz. 1978. Teratologic Evaluation of Inhaled Acrylonitrile Monomer in Rats. Toxicological Research Laboratory, Dow Chemical, Midland, MI. Quast, J.F., D.J. Schuetz, M.F. Balmer, T.S. Gushow, C.N. Park, and M.J. McKenna. 1980. A Two-Year Toxicity and Oncogenicity Study with Acrylonitrile Following Inhalation Exposure of Rats. Prepared by Toxicology Research Laboratory, Dow Chemical, Midland, MI., for the Chemicals Manufacturing Association, Washington, DC. Saillenfait, A.M., and J.P. Sabate. 2000. Comparative developmental toxicities of aliphatic nitriles: In vivo and in vitro observations. Toxicol. Appl. Pharmacol. 163(2):149-163. Sakurai, H., M. Onodera, T. Utsunomiya, H. Minakuchi, H. Iwai, and H. Mutsumura. 1978. Health effects of acrylonitrile in acrylic fibre factories. Br. J. Ind. Med. 35(3):219-225. Sweeney, L.M., M.L. Gargas, D.E. Strother, and G.L. Kedderis. 2003. Physiologically based pharmacokinetic model parameter estimation and sensitivity and variability analyses for acrylonitrile disposition in humans. Toxicol. Sci. 71(1):27-40. Willhite, C.C., V.H. Ferm, and R.P. Smith. 1981. Teratogenic effects of aliphatic nitriles. Teratology 23(3):17-23. Wilson, R.H., G.V. Hough, and W.E. McCormick. 1948. Medical problems encountered in the manufacture of American-made rubber. Ind. Med. Surg. 17(6):199-207. BENZONITRILE At its meeting held on October 26-29, 2010, the committee reviewed TSD on benzonitrile. A presentation on the TSD was made by Gary Diamond, of Syracuse Research Corporation. The following is excerpted from the Executive Summary of the TSD: 6

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Benzonitrile is a colorless liquid at ambient temperature and pressure and has an odor of volatile oil of almonds. The liquid is irritating to the skin and eyes, and the vapor is irritating to the eyes, nose, and throat…. AEGL-1 values are not recommended for benzonitrile because of insufficient data…. The AEGL-2 was based on labored breathing and poor coordination in rats exposed to 900 ppm for 3 hours…. The exposure of mice to 890 ppm for 2 hours resulting in 1/7 deaths was used as the basis of AEGL-3. A revised document should be submitted to the committee for review. AEGL-Specific Comments AEGL-1 Page 6, lines 6-9 (also see page 8, lines 5-8): “Symptoms of acute poisoning with benzonitrile are similar to those produced by other uncoupling agents, such as pentachlorophenol and dinitrophenol, and include fatigue, excessive sweating, thirst, pyrexia, anxiety, tachycardia, and hyperventilation. Symptoms may resolve on cessation of exposure. (HSDB 2003).” If these symptoms have been observed in humans, many of which are consistent with the AEGL-1 defintions, why do the authors state on page 15 that “no human data consistent with the definition of AEGL-1 were available.” HSDB is a secondary source. The authors should evaluate the primary source for these data and reassess whether the AEGL-1 value can be derived. If human data are in fact unavailable, the authors should consider whether data from “other uncoupling agents” could be used to derive AEGL-1 values for benzonitrile if acute effects are indeed similar across these agents. AEGL-2 Page 9, lines 28-39 (also see page 10, lines 29-42): In addition to poor coordination and labored breathing that occurred in rats and mice in the MacEwen and Vernot (1974) study described in Section 3.1, the authors reported the progression to prostration with an additional 30 min of exposure; that is, for 3.5 h at 900 ppm in rats and for 2.5 h in mice presumably at 700 ppm. Poor coordination and prostration data are pertinent to the derivation of AEGL-2 and should be added to the toxicity description in this section and in Table 2. However, is labored breathing an AEGL-2 end point? The TSD notes that, in mice exposed at 700 ppm for 4 h, “Congestion accompanied by edema was noted in the lungs of both exposure groups at necropsy.” In humans, labored breathing may equate to respiratory failure, which in cases, depending on the severity, may not be reversible without medical intervention. Please discuss whether labored breathing may be a more appropriate end point for AEGL-3 Page 15, line 29-30 states that a 2-fold modifying factor is used to “account for the sparse data base and potential delayed hepatic effects….” Although these are pertinent reasons for using a modifying factor, other crucial considerations are missing in this discussion. It is important to note that poor coordination is an end point to be prevented at the AEGL-2 because it can impair escape. The progression into prostration with only an additional 30 min of exposure lends further support for escape impairment (see details in Other Comments below). Thus, the use of a modifying factor should be sufficient for ensuring that these overt effects will not be likely to occur. To achieve sufficiency, at least two additional factors should be considered. One factor is the incidence of poor coordination at 900 ppm. Although the frequency of occurrence is not given in the study report, it appears to be prevalent for both rats and mice under the study conditions. The other factor is the extremely steep time-response relationship, showing progression into prostration with only an additional 30 min of exposure. Taken together, the modifying factor of 2 is probably not adequate. The authors should consider a modifying factor of 3 instead. 7

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AEGL-3 In selecting the POD at 890 ppm for 2 h that resulted in 14% fatality in mice (MacEwen and Vernot 1974), it should be noted that all 10 mice died at 700 ppm for 4 h. Of these, one died at 3.5 h of exposure. Thus, the default time-dose adjustment that brings the POD for 4 h at 445 ppm does not appear to be sufficiently low, as it is only 1.6-fold [=700/445] below a level that resulted in 100% death. Other Comments Cover page: Please provide the chemical structure on the title page. The reference HSDB (2003) is cited repeatedly in the Executive Summary and throughout the document (For example, page 8, lines 5, 8, and 17). Instead of citing the summary data, it is preferable that the original literature be reviewed and cited. Use of summary data gives the false impression that research was conducted more recently than in actuality. Page 7, Table S 1: Please indicate the exposure duration for the POD in the AEGL summary table when its concentration is mentioned Page 9, line 38-39: The sentence “However, multifocal areas of lymphoid hyperplasia.…” is incomplete. Please revise it. Page 12, Table 2: The following items need to be revised in Table 2:  Inhalation Section—In the rat exposure study (1900ppm) by Industrial Bio-Test (1970), the “Effect” cell should include the following sentence “two died at 2 h after exposure, one died on day 6 postexposure” in order to clarify that two post-exposure time points are included in “30% Mortality (3/10).”  Inhalation section—Provide information on mice effects from the MacEwen and Vernot (1974) study at the same level of detail as done for the rats, that is, indicate the irritation of extremities at the first hour of exposure, poor coordination, and labored breathing after 60-90 min. Also indicate that the one death at 890 ppm occurred on day 2.  Oral section—Unify all entries of dose in the unit of mg/kg. Page 10, lines 12-13: “Agaev (1977) reported the following ‘lethal concentrations for one-time exposure’ of benzonitrile in white rats: LC84 = 1,071 ppm, LC50 = 929 ppm, and LC16 = 738 ppm.” Please specify that the duration of exposure for the lethal concentrations was given. Comment References Agaev, F.B. 1977. Experimental substantiation of the maximum allowable concentration of benzonitrile for the air of the workplace [in Russian]. Gig. Tr. Prof. Zabol. 6:34-37. HSDB (Hazardous Substances Data Bank). 2003. Benzonitrile (CASRN 100 -47-0). TOXNET, Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet. nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB [accessed Dec. 8, 2010]. Industrial Bio-Test. 1970. Acute Toxicity Studies on Benzonitrile. Report to Velsicol Chemical Co. OTS 0571101. MacEwen, J.D. and E.H. Vernot. 1974. Acute inhalation toxicity of benzonitrile. Pp. 77-80 in Toxic Hazards Research Unit Annual Technical Report: 1974. AMRL-TR-74-78. Aerospace Medical Research Laboratory, Aerospace Medical Division, Air Force Systems Command, Wright-Patterson Air Force Base, OH. 8

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BORON TRIBROMIDE At its meeting held on October 26-29, 2010, the committee reviewed the TSD on boron tribromide. A presentation on the TSD was made by Lisa Ingerman, of Syracuse Research Corporation. The following is excerpted from the Executive Summary of the TSD: Based on the knowledge that boron tribromide hydrolyzes into hydrogen bromide, the boron tribromide AEGL-1 was based on the AEGL-1 value for hydrogen bromide…. No human or animal data on boron tribromide were available to derive AEGL-2 values. Therefore, the AEGL-2 values for boron tribromide were based on the AEGL-2 values for hydrogen bromide. For hydrogen bromide, the AEGL-2 values for the 30-minute, 1-, 4-, and 8-hour time points were based on severe nasal histopathology as well as low mortality in rats exposed to 1300 ppm hydrogen bromide or hydrogen chloride for 30 minutes…. The 10-minute AEGL-2 for hydrogen bromide was based on the RD50 (a decrease in the respiratory rate of 50%) of 309 ppm during a 10-minute exposure of male Swiss-Webster mice to hydrogen chloride…. No human or animal data on boron tribromide were available to derive AEGL-3 values.… The AEGL-3 values were derived by dividing the hydrogen bromide AEGL-3 values by three. The hydrogen bromide AEGL-3 values were based on 1-hour lethality data in a study with rats. A revised document should be returned to the committee for review. AEGL-Specific Comments AEGL-1 The committee approved the derivation of AEGL-1 values for boron tribromide. AEGL-2 The TSD correctly notes that human and animal data were unavailable for the derivation of hydrogen bromide values. The TSD authors used hydrogen bromide values to develop AEGL values for boron tribromide “[b]ased on the knowledge that boron tribromide hydrolyzes into hydrogen bromide. The committee is concerned that the 10-min hydrogen bromide (HBr) AEGL-2 value (150 ppm), used as the basis for AEGL-2 derivation of boron tribromide, may cause escape impairment to sensitive individuals. Stavert et al. (1991) stated that there is no quantitative difference between the toxicity of hydrogen chloride (HCl) and HBr. The 10-min HBr AEGL-2 value is 50% higher than the HCl value (100 ppm). In addition, the only human data on HBr irritation shows nasal and throat irritation at 6 ppm. The HBr AEGL-2, 10-min value is 25 times the nasal irritation level in healthy humans. We do not have information about the sensory effects of HBr at these concentrations, but we do have an RD50 (concentration that reduces the respiratory rate by 50%) for HCl of about 300 ppm. The committee suggests using the HCl AEGL-2 values across the board for HBr AEGL derivation with a rationale for using the more robust HCl database; also mention that this database is supported by the more limited HBr database. This change would significantly affect only the 10-min HBr AEGL-2 value and subsequently the boron tribromide AEGL-2,10-min value because the other AEGL-2 values for HCl and HBr are essentially the same. 9

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AEGL-3 The committee approved the derivation of the AEGL-3 values for boron tribromide. Other Comments Page 8, Table 2: Vapor pressure data should be reported in the same units (either torr or mmHg, not both). Choice of unit should be consistent across all AEGL documents. Comment References Stavert, D.M., D.C. Archuleta, M.J. Behr, and B.E. Lehnert. 1991. Relative acute toxicities of hydrogen fluoride, hydrogen chloride, and hydrogen bromide in nose- and pseudo-mouth-breathing rats. Fundam. Appl. Toxicol. 16(4):636-655. BZ At its meeting held on October 26-29, 2010, the committee reviewed the TSD on agent BZ (3-quinuclidinyl benzilate). A presentation on the TSD was made by Lisa Ingerman, of Syracuse Research Corporation. The following is excerpted from the Executive Summary of the TSD: Data in humans did not define no-effect exposures or exposures that would result in effects consistent with the AEGL-1 definition. Therefore, AEGL-1 values for BZ are not recommended. For AEGL-2 development, a 3-fold reduction of the ICt50 value of 60.1 mg- min/m3 (60.1 mg-min/m3  3 = 20 mg-min/m3 or 4 mg/m3; equivalent to 0.004 mg/L) was considered an estimate of the threshold for incapacitating effects.… Due to the lack of data regarding longer exposure durations and uncertainties regarding the effects of such exposures, AEGL-2 values for 4-hour and 8-hours were not recommended…. The AEGL-3 values for BZ were derived using 3,700 mg-min/m3 as the point-of-departure. This is a 10-fold reduction of the LCt50 value for monkeys… A revised document should be submitted to the committee for review. AEGL-Specific Comments AEGL-1 The authors should reconsider derivation of an AEGL-1 value or provide a better explanation for not deriving an AEGL-1 value. The committee finds that an AEGL-1 derivation may be possible by using the 95% lower-confidence ED50 (dose of a substance causing an effect in 50% of the exposed population) for Total Response Inventory (TRI) 4.0 effects in humans (page 10, Section 2.2, Nonlethal Toxicity) as an appropriate POD. If the lower-confidence ED50 for TRI 4 is used as a POD, please consider (a) UF = 1 for interspecies because it is based on human data; or (b)UF = 10 for intraspecies due to the range of toxic effects (primarily psychological). In considering use of the 4.0 TRI, that authors should investigate variability in the TRI data and whether the 95% CI is too low, particularly with an intraspecies UF of 10. In considering use of the 4.0 TRI, that authors should investigate variability in the TRI data and whether the 95% CI is too low, particularly with an intraspecies UF of 10. 10

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AEGL-2 The ICT50 (concentration and time of an exposure that incapacitates 50% of an exposed population) is an AEGL-2 effect. The authors should consider the lower 95% confidence level of the ICT50 (41.3 mg-min/m3) or, if available, the 99% lower confidence level of the ICT50 for AEGL-2 derivation. This is also supported by the lower 95% confidence limit (66.2 mg-min/m3) for the ED50 (90.5 mg-min/m3) for TRI 4.0 effects. The TRI 4.0 effects are mild and below those of an AEGL-2 effect. The authors should consider using an intraspecies UF of 10. The uncertainty in dosimetric parameters seems to support an UF of 10. If the authors choose to leave the UF at 3, a better justification is needed. Because of the short 5-min exposure period, the authors could consider dropping the 1-h value for AEGL 2. If that is done, discussion needs to be added explaining the rationale. AEGL-3 Page 20, line 45, to page 21, line 3: “Although a 3-fold reduction of the LC50 (lethal concentration in 50% of exposed population) is routinely considered an appropriate estimate of the lethality threshold for chemicals with known steep exposure-response relationships (NRC 2001), little is known about the exposure-response curve for BZ. Therefore, the 10-fold reduction is considered more defensible.” A 10-fold reduction deviates from the SOP. Please review SOP Section 2.2.2.3.2 for applicability. The committee recommends a 3-fold reduction from data on the most sensitive species with the most appropriate uncertainty factors. If the experimental conditions do not apply, the authors should identify a different POD. The authors should consider using an intraspecies UF of 10. The uncertainty in dosimetric parameters and toxic end points support an UF of 10. If left at 3, better justifcation is needed. The authors should eliminate the modifying factor. Modifying factors represent an adjustment for uncertainties in the overall database or for known differences in toxicity among structurally similar chemicals. Although not a rich database, there are no apparent uncertainties for lethality with the exception of the short durations (see comment on AEGL-3 1-h value below). Because of the short 5-min exposure period, the authors should consider dropping the 1-h value for AEGL 3. If that is done, discussion needs to be added explaining the rationale. Other Comments The accepted abbreviation for the Department of the Army is ‘DA’. Replace DoA with DA throughout the TSD. Page 7, lines 18-19: What is the basis for the statement “the anticholinergic mechanism by which BZ operates is not likely to vary by an order of magnitude”? Page 8, lines 12-13; page 10, lines 11-12. The authors cite the following reference: “Hoenig, S.L. 2007. Compendium of Chemical Warfare Agents. New York: Springer.” Is this reference peer reviewed? If possible, the authors should cite the source document rather than a compendium. Page 10, lines 23-24: The sentence “Test candidates were also selected based upon evaluation by the Minnesota Multiphasic Personality Inventory and results of psychological interviews” seems out of place. It describes how candidates were selected, while the previous sentence discusses how tests were conducted. The sentence should be placed in the appropriate context near the beginning of the paragraph. Page 11. lines 2-3: Was there any discussion of deposition and release from clothing contributing to exposure? 11

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AEGL-2 The committee approved the derivation of AEGL-2 values for silane. AEGL-3 The committee approved the derivation of AEGL-3 values for silane. Other Comments Page 5, lines 25-26: “At the next higher concentration, 5000 ppm, renal lesions were noted after both the two day and two week observations, making 2500 ppm the NOEL for irreversible effects at 4 hours.” Please clarify that at 5,000 ppm, no reversibility was observed during the 2-week observation period, rather than call the renal lesions “irreversible”. SULFURIC ACID, OLEUM, AND SULFUR TRIOXIDE At its meeting held on October 26-29, 2010, the committee reviewed the TSD on sulfuric acid, oleum, and sulfur trioxide. A presentation on the TSD was made by Lisa Ingerman, of Syracuse Research Corporation. The following is excerpted from the Executive Summary and Introduction of the TSD: In essence, the health effects of sulfuric acid are related to the direct irritation of the respiratory tract…. The AEGL-1 values are based on respiratory irritation observed in many human volunteer studies at concentrations higher than 0.2 mg/m3…. 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 the 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 are converted to sulfuric acid at ambient conditions. A revised document should be submitted to the committee for review. AEGL-Specific Comments Although the values for all three AEGL levels appear to be reasonable, the rationale that the authors used to reach these numbers is not well-justified and, in some cases, not correct. The authors need to revise the rationale for the issues outlined in Other Comments below. Other Comments The rationale of citing only three air-pollution epidemiologic studies in this Interim TSD is not clear. There are many similar studies that were applicable to the derivation of AEGLs that need to be included for discussion. 49

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The number of human subjects participating in sulfuric acid studies exceeds 1,000. However, only the results of 96 healthy and 85 asthmatic subjects were summarized in the Interim TSD. Justification is needed to explain why other studies were excluded. Perhaps a summary of the other studies needs to be included. Notably missing studies are Utell (1983) and Koenig (1983). Page 4, lines 7-6: “The author linked these increases to the high ambient sulfur trioxide concentrations....” Please clarify whether the ambient sulfur trioxide concentrations resulted from accidental release or persistent industrial effluent. This case report could be relevant to AEGL development if sulfur trioxide release was accidental. Page 4, lines 37-39: The authors describe the studies as of “adequate quality” (line 39) which suggests that these studies are acceptable, but could have been conducted or reported in a better manner. Is this the intention of the authors? If the studies were well-conducted, they should be described as “high quality.”Also, it is unclear why these specific studies were described in such detail (page 4, line 42- page 6, line 49), particularly if they are only of “adequate” quality. The authors should consider providing an overview summary of the data in the tables. For example, say that exposures for x to y hours at concentrations of a to b did not affect PFT in normal adults, and so forth. Perhaps consider moving Section 2.7 to this discussion. Page 5, lines 47-51: Please revise the description of the Linn et al. study (1989) to say that the particles were fog particles and hypo-osmotic. They were not regular acid droplets. Page 7, lines 19-23: “There was a significant difference in the incidence of chronic bronchitis/chronic bronchial asthma between the workers and controls. The VC was not affected by exposure. The FEV1 decreased by 82 ml (an estimated decrease of 2%) during the shift of exposed workers, but this decrease is small compared to the normal diurnal variation in FEV1 of approximately 10%.” The authors should distinguish functional change in a population vs. individual change. Since diurnal variation or other variations most likely occurred in both the control and exposed groups, a small, statistically significant change when compared with the controls should be treated as relevant, even though physiologically, it may not be important. Page 7, lines 25-37: Could the lack of effect be due to the healthy worker effect? Also, larger particles are not effective in inducing pulmonary toxicity. Hygroscopic growth would probably result in these particles being deposited in the nasopharyngeal region, not deep in the conducting or respiratory airways. It is a mistake to use the results of fog acid particle studies to say that size is not a factor. Those fog particles are hypo-osmotic and contain little acid. If left in dry air, they will become submicrometer in size. The larger particles found in the lead acid plants were more likely to be concentrated acid and to absorb water vapor readily. Page 27, lines 8-10: Epidemiologic studies of acid aerosol should be a separate section or not discussed at all. For other epidemiologic studies, see Chen et al. (2007) (full citation provided below). Page 27, lines 37-46: These two paragraphs are confusing. They include assessments of both epidemiologic studies in the general public and occupational studies without distinguishing which of these demonstrated associations between sulfuric acid exposure and cancer. Please revise this section to make it clear whether both types of studies demonstrated a causal relationship or whether a relationship is observed in just one type of study. Page 28, lines 17-19: “Studies examining lung function in healthy and asthmatic individuals found statistically significant alterations in several parameters.... However, the magnitude of the alterations were within normal variation.” These sentences do not make sense. If the changes were within normal variation than how can they be statistically significantly associated with acid exposure? Please clarify. Page 27, lines 19-25: “However, the magnitude of the alterations were within normal variation. For FEV1, changes of less than 12% in an individual are not considered clinically significant (Pellegrino et al. 2005). Measurements of airway resistance and conductance have a relatively poor reproducibility (Tattersfield and Keeping 1979). Hruby and Butler (1975) reported a diurnal variation of 40% of the mean for SRAW readings for a group of 6 subjects; Tattersfield and Keeping (1979) reported that other studies have found 12-17% variation in day-to-day readings. Thus, changes in SRAW and SGAW of less 50

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than 20% were considered to be within the range of normal variation.” Clinical significance is more applicable to assessment of whether an adverse effect is meaningful for an individual subject. However, in control studies, statistical significance should be treated differently (see above). Page 28, line 32-33: “Conflicting results between individual studies may have been due to differences in the tracer aerosol particle size (Spektor et al. 1989)” This comment is misleading. Tracer particle size differences may have resulted in different studies measuring clearance from different regions of the respiratory tract. Please revise this comment. Page 28, line 34-35: “The increased mucociliary clearance observed at lower sulfuric acide concentrations may be due to subthreshold irritation....” What is subthreshold irritation? If exposure resulted in a change in some function, how can it be subthreshold? In addition, both increased and decreased clearance indicates an effect, and the justification for excluding increased clearance rate is not valid. Page 28, lines 40-46: This section describes the results of occupational studies, and the comment that “the concentrations in these studies would not induce severe short-term toxic effects or impair the subjects’ ability to escape” is misleading. In general, the particle size of the acid in occupational settings would be much larger than that during some exposure to the general population. Thus, there could be short-term effects at some of these occupational concentrations with smaller-sized acid particles. Please revise this section to discuss possible toxicity caused by smaller-sized particles. Page 45, Section 4.2: There were studies that investigated how sulfuric acid affects intracellular pH regulation that may be relevant to cellular function and macrophage phagocytosis and may be applicable to physiologic change. Page 46, lines 33-39: The Interim TSD dismissed many studies using guinea pigs as an animal model. Although it is debatable to dismiss guinea pigs as a super-sensitive model not applicable to humans (including those who have asthma), some studies that had used this species to investigate the effect of particle size and mechanisms should be included. It is possible that a super-sensitive human population exists and could respond to sulfuric acid similar to guinea pigs. Better justification is needed to exclude data derived using guinea pig. Page 49, line 20-48: The authors dismiss several controlled clinical studies with changes that were smaller than “normal” physiologic range. The “normal” physiologic range that was measured during routine medical examinations and would be influenced by many factors—environment where these measurements were taken, environmental factors that subjects experienced prior to these measurements, and other host factors. However, in controlled clinical studies, many of these factors were minimized, and any changes seen that were different from the controls’ changes should be taken as changes induced by the exposure. Furthermore, even though the changes from the controls were not clinically significant, changes in respiratory parameters over a control group have significance because there must be a mechanistic influence caused by exposure that leads to these changes. The document should be revised to reflect these comments. Page 49, line 26, to page 55, line 2: “Although some conflicting results have been reported, increases in mucociliary clearance have generally been observed at exposures of 0.1 to 0.5 mg/m3; increase in clearance, which is likely due to subthreshold irritation, was not considered an AEGL-1 effect” The change in mucus clearance produced by sulfuric acid is similar to that produced by cigarette smoke exposure, that is, low-concentration accelerated clearance and high-concentration retarded clearance. Both types of change should be considered irritant effects. Mucus clearance is a sensitive end point, and changes in this parameter have been shown to be reproducible (rather than erratic as described in the Interim TSD) across species in response to such irritants as sulfuric acid aerosol and cigarette smoke. The concentrations that elicit changes in mucus clearance should be included in the derivation of AEGLs. Page 50, line 34: “However, this termination does not necessarily reflect an impaired ability to escape.” Perhaps if the exposure continued for a bit at this concentration, there would be impaired ability to escape. This sentence should be revised to reflect this possibility. 51

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Page 50, line 36: “Occupational data indicate that workers can complete their normal work shifts at sulfuric acid concentrations of 26-25 mg/m3 (El-Sadik et al. 1972),”. This statement is not relevant and should be deleted. The particle size in this study is large and not relevant to real-world exposure scenarios. Page 51, line 20: “The results of the study by Linn et al. (1989) do not provide an adequate point of departure for AEGL-2 because of the worst case exposure conditions and because the termination by some of the subjects was due to sub-AEGL-2 effects:” The authors note that four asthmatic subjects in the Linn study could not complete one or more of the exposures (page 6, lines 25-27). Although control conditions (exercise) also produced symptoms in asthmatic subjects, it is not clear whether these four subjects completed all exercise period during the control experiments. If the four subjects were able to complete the control experiments, but not the acid exposures, the Linn study is very relevant to setting AEGL-2 values. Please clarify which experiments the four were able to complete. Page 52, Section 6 (Data Analysis for AEGL-2): The authors dismiss the notion that the size of sulfuric acid particles can be a factor in toxicity, and cited Linn et al. (1989) as evidence. Citing Linn’s study to say size is not relevant is not correct. There are many studies that showed that size matters, especially for sulfuric acid. Linn et al. (1989) was investigating acid fog particles with particle sizes ranging from 1 to 20 µm, however, these particles need to be produced at 100% relative humidity to maintain their size and would be very different from those produced in the acid battery plants where up to 20-µm size particles were present. Particles in the Linn study were also hypo-osmotic, which produced very different effects from those of normally hyper-osmotic sulfuric acid droplets. It is not only inappropriate to use industrial exposure to extrapolate to exposure to the general public, it is very difficult to conclude that particle size has no effect. Those particles measured in the battery plants would have grown to even larger particles and would be deposited on the upper airway without ever reaching the lower airways. There were several studies specifically investigating particle size, and these studies need to be included in this document. Discussions of size-dependent toxicity of sulfuric acid aerosol should reference Lippmann et al. (1987) (full citation provided below). Page 52, lines 36-37: “... no irreversible or disabling effects were observed follwing acute exposure to 20.8 mg/m3 for 30 minutes or 39.4 mg/m3 for 60 minutes (Sim and Pattle 1957).” The issue of particle-size differences is not addressed at all, and it can make a significant difference when setting the AEGL. If the size is large, most deposition would be in the upper respiratory tract, and this factor could have less impact on escape potential than deposition in the lower tract, especially for those who have asthma. Comment References Chen, L.C., G.D. Thurston, and R.B. Schlesinger. 2006. Acid aerosols as a health hazard. Pp. 111-161 in Air Pollution and Health, J. Ayres, R.L. Maynard, and R. Richards, eds. London: Imperial College Press. El-Sadik, Y.M., H.A. Osman, and R.M. El-Gazzar. 1972. Exposure to sulfuric acid in manufacture of storage batteries. J. Occup. Med. 14(3):224-226. Hruby, J., and J. Butler. 1975. Variability of routine pulmonary function tests. Thorax 30(5):548-553. Koenig J.Q., Pierson W.E., and M. Horike. 1983. The effects of inhaled sulfuric acid on pulmonary function in adolescent asthmatics. Am. Rev. Respir. Dis. 128(2):221-225. Linn, W.S., E.L. Avol, K.R. Anderson, D.A. Shamoo, R.C. Peng, and J.D. Hackney. 1989. Effect of droplet size on respiratory responses to inhaled sulfuric acid in normal and asthmatic volunteers. Am. Rev. Respir. Dis. 140(1):161-166. Lippmann, M., J.M. Gearhart, and R.B. Schlesinger. 1987. Basis for a particle size-selective TLV for sulfuric acid aerosols. Appl. Ind. Hyg. 2(5):188-199. Pellegrino, R., G. Viegi, V. Brusasco, R.O. Crapo, F. Burgos, R. Casaburi, A. Coates, C.P. van der Grinten, P. Gustafsson, J. Hankinson, R. Jensen, D.C. Johnson, N. MacIntyre, R. McKay, M.R. Miller, D. Navajas, O.F. Pedersen, and J. Wanger. 2005. Interpretive strategies for lung function tests. Eur. Respir. J. 26(5):948-968. 52

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Sim, V.M., and R.E. Pattle. 1957. Effect of possible smog irritants on human subjects. JAMA 165(15):1908-1957 Spektor, D., B.M. Yen, and M. Lippmann. 1989. Effect of concentration and cumulative exposure of inhaled sulfuric acid on tracheobronchial particle clearance in healthy humans. Environ. Health Perspect. 79:167-172. Tattersfield, A.E., and I. Keeping. 1979. Assessing change in airway caliber-measurement of airway resistance. Br. J. Clin. Pharmacol. 8(4):307-319. Utell, M.G., Morrow P.E., Speers D.M., Darling J., and R.W. Hyde. 1983. Airway responses to sulfate and sulfuric acid aerosols in asthmatics. An exposure-response relationship. Am. Rev. Respir. Dis. 128(3):440-450. TEAR GAS At its meeting held on October 26-29, 2010, the committee reviewed the TSD on tear gas. A presentation on the TSD was made by Lisa Ingerman, of Syracuse Research Corporation. The following is excerpted from the Executive Summary of the TSD: The AEGL-1 values were based on human exposure to 1.5 mg/m3 for 90 minutes (Punte et al. 1963). All four subjects could tolerate the exposure, but experienced eye and nose irritation and headache…. The AEGL-2 values were based on human exposure to 1.5 mg/m3 for 90 minutes (Punte et al. 1963). All four subjects could tolerate the exposure, but experienced eye and nose irritation and headache…. AEGL-3 values were based on the threshold for lethality at each AEGL-3 exposure duration calculated using the probit-analysis based dose-response program. A revised document should be returned to the committee for review. AEGL-Specific Comments AEGL-1 The committee is concerned that the existing AEGL-1 values lack sound scientific foundation and supporting studies. The TSD authors should evaluate the following alternatives for the derivation of AEGL-1, and provide adequate justification for their choice in the TSD: 1. Justify selection of the modifying factor. Page 43, lines 7-9: “Because the observed effects are above those defined by AEGL-1, a modifying factor of 10 will be applied to reduce the point-of-departure from a LOAEL to a NOAEL for AEGL-1 effects.” Section 2.6.2 (page 92) of the SOP states that in “instances in which the adverse effects used to set the AEGL value are more severe than those described in the AEGL definitions,” a modifying factor of 2 or 3 should be considered. Why did the authors choose a modifying factor of 10? Reduction from LOEL to NOEL using a modifying factor of 10 instead of 2 or 3 needs additional justification. 2. Select an alternate POD. Page 10, lines 11-14: “In a review article, Blain (2003) reported a TC50 (defined as the concentration required to obtain no more than a perceptible effect on 50% of the population exposed to the gas for 1 minute) of 0.004 mg/m3 for ocular irritation and 0.023 mg/m3 for airway irritation.” The authors should consider the TC50 of 0.004 mg/m3 for perceptible effects as a reasonable POD for AEGL-1 values, if the original article can be referenced. 3. Do not recommend AEGL-1 values. On the basis of the chosen PODs, the difference in AEGL- 1 and AEGL-2 effects and in recommended concentrations is small. However, there is a large increase in concentration (approximately 50 times) leading to AEGL-3 effects. Rather than using a modifying factor, the authors should consider not providing an AEGL-1. 53

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AEGL-2 The Punte et al. (1963) study of four human subjects was used to develop AEGL-2 values. The exposure time was short, but data were inconsistent among the four individuals. Ocular irritation developed in 20 min of 24 min in two individuals and in 70 min of 75 min for the remaining two individuals. This result indicates a wide time diversity in susceptibility. The authors report that “all four subjects could tolerate the exposure, but experienced eye and nose irritation and headache.” (page 44, lines 7-8, and elsewhere). AEGL-2 effects include “irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape.” Are the effects described in the Punte study a LOAEL for AEGL-2 effects? If the TLV ceiling is listed as 0.05 ppm, why is there such discrepancy between the AEGL 2 value and the TLV ceiling? It would seem that the health effect is more an intolerance to tear gas based on the individual susceptibilities of the four subjects. With ocular irritation at 20 min, how would it affect escape? Would it have an impairement affect on escape? The ERPG-2 is one-fifth the proposed AEGL-2 value but is based on the same end point. The basis for the ERPG-2 should be reviewed to determine whether the assumption of no individual variability is sufficiently robust and whether the intraspecies UF of 3 is appropriate in this case. Evaluate this in light of the 30-min AEGL-2 being less than the IDLH. Could it be that at exposures greater than 30 min effects other than direct irritating effects come into play? This discussion needs to address the category plots on page 64. For animals, disabling effects (AEGL-2) and death (AEGL-3) overlap. How does this overlap relate to human exposures? The authors should reconsider Beswick et al. (1972) for the development of AEGL-2 values (pages 14-15).The Beswick study included more subjects than Punte et al. (1963), and some subjects experienced nausea and vomiting in addition to occular irritation. AEGL-3 The authors should consider whether a benchmark concentration approach could be used to derive AEGL-3 values (see SOP, Section 2.2.1). Other Comments Page 8, lines 5 and 8: The authors use a time-scaling value of 0.704. Is this an appropriate number of significant figures? SOP 2.9.1 Mathematical Rounding of AEGL Values states two significant figures for AEGLs; this factor should also apply to time-scaling. Page 9, line 38: “When released to the air CS will exist in both vapor and aerosol form (HSDB 2005)” What is the aerosol particulate size distribution? The size distribution is an important factor affecting toxic effect location. Also, the Hazardous Substances Data Bank is a secondary reference. What is the primary source for this information? Whenever possible, the primary source should be cited. Page 44, Section 7, Data Analysis for AEGL-3: Provide a table summarizing the AGEL-3 value derived from each species compared with the value derived from the high-end human exposures based on case reports. The narrative provides a description of this analysis, but it is not easy to compare across species. In addition, please explain why the guinea pig is more sensitive than the other species. Page 46, Section 8.2, Comparison with Other Standards and Guidelines: The authors need to provide some discussion regarding the considerable differences in some of the values in comparison to the derived AEGLs. For example, the IDLH value is so much different from the AEGL values; the ERPG-3 value is twice the AEGL-3 value. Please provide an explanation. Page 43, lines 11-13 (also page 44, lines 9-13, and page 45, lines 23-27): Delete the sentence about the UF of 3 being supported by responses of individuals with jaundice, hepatities, or peptic ulcers. The sentence is confusing and irrelevant. 54

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Appendix B: Please show the plot for the time-scaling. Comment References Beswick, F.W., P. Holland, and K.H. Kemp. 1972. Acute effects of exposure to orthochlorobenzylidene malononitrile (CS) and the development of tolerance. Br. J. Ind. Med. 29(3):298-306. Blain, P.G. 2003. Tear gases and irritant incapacitants. 1-chloroacetophenone, 2-chlorobenzylidene malononitrile and dibenz[b,f]-1,4-oxazepine. Toxicol. Rev. 22(2):103-110. HSDB (Hazardous Substances Data Bank). 2005. 2-Chlorobenzalmalononitrile (CASRN 2698-41-1). TOXNET, Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB [accessed Feb. 28, 2008]. Punte, C.L., E.J. Owens, and P.J. Gutentag. 1963. Exposures to ortho-chlorobenzylidene malononitrile: Controlled human exposures. Arch. Environ. Health 6:366-374. THIONYL CHLORIDE At its meeting held on October 26-29, 2010, the committee reviewed the TSD on thionyl chloride. A presentation on the TSD was made by Julie Klotzbach, of Syracuse Research Corporation. The following is excerpted from the Executive Summary of the TSD: Data are not available from human or animal studies to derive AEGL-1 values. Therefore, AEGL-1 values are not recommended. Rats exposed to 71 ppm thionyl chloride for one hour experienced swollen noses and dyspnea (Pauluhn 1987). These are toxic responses but not irreversible or incapacitating effects and will not impair ability to escape. The AEGL-2 values are derived from this data…. The AEGL-3 values were based upon the highest concentration causing no lethality in rats exposed to thionyl chloride for one hour. A revised document should be submitted to the committee for review. AEGL-Specific Comments AEGL-1 As stated in the TSD (page 8, lines 20-22), thionyl chloride hydrolyzes upon contact with water, yielding sulfur dioxide and hydrogen chloride. Most, if not all, of the effects of thionyl chloride are probably caused by these hydrolysis products. The authors should consider developing AEGL-1 values based on SO2 data. AEGL-2 There are two primary data sets best suited to develop both AEGL-2 and AEGL-3 values—the Pauluhn study (page 12, lines 5-14) and the Nachreiner study (page 12, lines 16-26). AEGL-2 values should be recalculated based on the Nachreiner study. As noted in the TSD, there appears to be a relationship between LC50 and the relative humidity used in the experiment, lower humidity leading to increased toxicity and lower LC50 values. This finding suggests that either the parent compound is more toxic than the hydrolysis products or that the delay in hydrolysis (half-life of 5 min at 53% relative humidity per Nachreiner) leads to deeper deposition in the lungs of the hydrolysis products. Both possibilities regarding hydrolysis should be discussed in the text. Because of these possibilities, the 55

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Nachreiner study, with the lowest humidity, is probably a better POD; the Pauluhn study could be used as support. AEGL-3 The committee recommends the use of Pauluhn (1987) for development of AEGL-3 values. Please see comment above under AEGL-2. Other Comments Page 8, lines 20-23: Thionyl chloride hydrolyzes upon contact with water, yielding sulfur dioxide and hydrogen chloride, and most, if not all, of the effects of thionyl chloride are probably caused by these hydrolysis products. However, the dose-effect (or concentration-effect) relationship for inhaled thionyl chloride may differ from that for inhaled sulfur dioxide and hydrogen chloride, as the former exposure will result in deeper deposition in the respiratory tract and more severe effects. This notion is supported by the lower rat LC50 values obtained at low relative humidity (Nachreiner 1993), as compared with higher humidity (Pauluhn 1987). Page 15, lines 6-8: “Following inhalation, sulfur dioxide is distributed throughout the body after dissolving into surface fluid. Some remains in the respiratory system for a week or more following exposure.” Please explain how SO2 can remain in the lung for a week or more. Page 15, Section 4.2 (Mechanism of Toxicity): On the basis of data from the three main studies indicating a toxicity difference related to relative humidity, the following paragraphs should be added to the discussion: Sulfur dioxide acts on the respiratory system via stimulation of bronchoconstriction and mucus secretion in the upper airways. It injures cells lining the airway passages and causes mucus-secreting goblet cells to proliferate. These two events result in airway narrowing and increased airflow resistance (Costa 2001). Inhaled hydrogen chloride irritates the respiratory tract following a latency period of several hours. Following exposure, the epithelial barrier in the alveolar zone breaks down and begins to leak, causing pulmonary edema (Witschi and Last 2001).” Page 16, Section 6 (Data Analysis for AEGL-2): Three additional items should be inserted into the discussion on AEGL derviation: (1) the equation showing the hydrolysis reaction of thionyl chloride; (2) a summary table comparing the Kinkead and Einhaus (1984), Pauluhn (1987), and Nachreiner (1993) studies and including the relative humidity present in each; and (3) a table of the AEGL values for HCl and SO2 (currently a part of Table 8). Page 16, lines 36-38, and page 18, lines 9-11: “An uncertainty factor of 10 was used for intraspecies variation due to the wide variability in response to sulfur dioxide between healthy and asthmatic humans.” The gender difference noted in the Nachreiner study (page 12. lines 20-22) should be listed as support for the intraspecies UF of 10 used. Comment References Costa, D.L. 2001. Air pollution. Pp. 979-1012 in Casarett & Doull’s Toxicology: The Basic Science of Poisons, 6th Ed., C.D. Klaassen, ed. New York: McGraw-Hill. Kinkead, E.R., and R.L. Einhaus. 1984. Acute Toxicity of Thionyl Chloride Vapor for Rats. AFAMRL-TR-84-069. ADA148952. Air Force Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH. Nachreiner, D.J. 1993. Thionyl Chloride: Acute Vapor Inhalation Toxicity Study in Rats. Union Carbide Chemicals and Plastics Company, Inc., Export, PA. 56

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Pauluhn, J. 1987. Study for Acute Inhalation Toxicity in Rats in Accordance with OECD Guideline No. 403 (Exposure: 1 × 1 Hour). Bayer AG Report No. 15403. Leverkusen, Germany: Bayer AG. Witschi, H.R., and J.A. Last. 2001. Toxic responses of the respiratory system. Pp. 515-534 in Casarett & Doull’s Toxicology: The Basic Science of Poisons, 6th Ed., C.D. Klaassen, ed. New York: McGraw-Hill. TRIMETHOXYSILANE AND TETRAMETHOXY SILANE At its meeting held on October 26-29, 2010, the committee reviewed the TSD on trimethoxysilane and tetramethoxysilane. A presentation on the TSD was made by Mark Follansbee, of Syracuse Research Corporation. The following is excerpted from the Executive Summary of the TSD: AEGL-1 values were not derived for either trimethoxysilane or tetramethoxysilane because of limited data. AEGL-2 values for trimethoxysilane were derived by taking 1/3 of AEGL-3 values.… AEGL-3 values were determined by using mortality data from 1 and 4 hour LC50 rat inhalation studies…. AEGL-2 values for tetramethoxysilane were derived from a repeat dose inhalation study in which rats were exposed for 6 hours/day, 5 days/week for 28 days at concentrations up to 45 ppm…. AEGL-3 values were derived from an LC50 4-hour rat inhalation study. A revised document should be submitted to the committee for review. AEGL-Specific Comments AEGL-1 AEGL-1 values were not derived for either trimethoxysilane or tetramethoxysilane because of limited data. A recommendation is to consider developing AEGL-1 values based on AEGL-2 values by using an UF between 3 and 10. This comment is largely discretionary. The 1-h ERPGs for trimethoxysilane were recently (2010) set at 0.5 ppm based on a 90-day exposure study in rats. The authors should review the supporting literature for the ERPG as a possible source to support the development of AEGL-1 values. AEGL-2 The committee approves the derivation of AEGL-2 values for trimethoxysilane. Page 21, lines 36-37: For tetramethoxysilane “A total uncertainty factor of 30 was used. Three was used for the interspecies uncertainty factors because in a five-day inhalation study with trimethoxysilane, a structural analog, effects were similar in rats, mice and hamsters.” A UF of 3 may be overly conservative, given the similarity in effects across species. The committee suggests that the authors use a UF of 1 for interspecies. AEGL-3 The committee approves the derivation of AEGL-3 values for trimethoxysilane. Page 23, lines 15-17: For tetramethoxysilane, a UF of 3 was used for interspecies, although “in a five-day inhalation study with trimethoxysilane, a structural analog, effects were similar in rats, mice and hamsters.” A UF of 3 may be overly conservative. The committee suggests that a UF of 1 be used instead. 57

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This number is also supported by evidence from the Kolesar et al. (1989) (used to derive the AEGL-2 values) study in which rats survived a 28-day, 6 h/day exposure at 30 ppm (although rats died at 45 ppm). Comment References Kolesar, G.B., W.H. Siddiqui, R.G. Geil, R.M. Malczewski, and E.J. Hobbs. 1989. Subchronic inhalation toxicity of tetramethoxysilane in rats. Fundam. Appl. Toxicol. 13(2):285-295. TRIMETHYLBENZENES At its meeting held on October 26-29, 2010, the committee reviewed the TSD on 1,3,5- trimethylbenzene, 1,2,4-trimethylebenzene, and 1,2,3-trimethylbenzene. A presentation on the TSD was made by Julie Klotzbach, of Syracuse Research Corporation. The following is excerpted from the Executive Summary of the TSD: For derivation of AEGL values, all available data for the individual TMB isomers were considered…. The most appropriate animal data for derivation of AEGL-1 are the neurotoxicity studies (Korsak et al. 1995, Korsak and Rydzyński 1996)…. Rats repeatedly exposed to 2000 ppm for 6 hours exhibited irritation, respiratory difficulty, lethargy, and tremors (Gage 1970); therefore 2000 ppm was chosen as the basis for deriving the 10-min, 30-min, 1-hour, 4-hour, and 8-hour AEGL-2 values…. Data are insufficient for derivation of AEGL-3 values for TMB. One study showing lethality in rats did not include data adequate for a concentration-response assessment. This document can be finalized. AEGL-Specific Comments The committee approves the derivation of the AEGL-1, AEGL-2, and AEGL-3 values for trimethylbenzenes. Comment References Gage, J.C. 1970. The subacute inhalation toxicity of 109 industrial chemicals. Br. J. Ind. Med. 27(1):1-18. Korsak, Z., and K. Rydzyński. 1996. Neurotoxic effects of acute and subchronic inhalation exposure to trimethylbenzene isomers (pseudocumene, mesitylene, hemimellitene) in rats. Int. J. Occup. Med. Environ. Health 9(4):341-349. Korsak, Z, R. Swiercz, and K. Rydzynski.1995. Toxic effects of acute inhalation exposure to 1,2,4-trimethylbenzene (pseudocumene) in experimental animals. Int. J. Occup. Med. Environ. Health 8(4):331-337. VINYL CHLORIDE At its meeting held on October 26-29, 2010, the committee reviewed the TSD on vinyl chloride. A presentation on the TSD was made by Ernest Falke, of the U.S. Environmental Protection Agency. The following is excerpted from the Executive Summary of the TSD: 58

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The AEGL-1 was based on the study of … 4-7 volunteers, two individuals experienced mild headache during 3.5 and during 7.5 hours (3.5 hours, 0.5 hours break, 3.5 hours) of exposure to 491 ppm. The time of onset of headaches is not clearly stated and was assumed to be after 3.5 hours…. The AEGL-2 was based on prenarcotic effects observed in human volunteers. After 5 minute exposure to 16,000 ppm VC [vinyl chloride], 5 of 6 persons showed dizziness, lightheadedness, nausea, and visual and auditory dulling…. The AEGL-3 was based on cardiac sensitization and the no effect level for lethality. This document can be finalized. AEGL-Specific Comments The committee approves the derivation of the AEGL-1, AEGL-2, and AEGL-3 values for vinyl chloride. COMMENTS PERTAINING TO ALL TSDS Whenever substantial discrepancies are found between AEGL values and other guideline values (e.g., IDLHs, STELs, and WEELs), the possible reasons should be explored and discussed in the text. The SOP, Appendix J, page 201, states, “A summary discussion of important comparisons should be presented in the text and the values for recognized standards and guidelines, if available, should be presented in the table.” Reliance on review articles and compendia appears to have increased. The SOP states that the primary literature must be used (SOP, page 51) for key studies, supporting data, and information important to the derivation of an AEGL value. If the summarization of findings from a primary reference as described in a secondary source is used, the citation needs to be clear that it is not coming from the primary literature, that is, a paper “as cited in.” If a reference is unpublished, the citation should make clear how the information can be obtained by others. The authors need to make sure the literature on the chemicals have been updated for documents that have been several years in the AEGL-development process. The date of the most recent literature review should be included in the TSD. The chemical structure of the compounds should be included on the title page of every TSD. 59