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National Research Council (US) Committee on Acute Exposure Guideline Levels; National Research Council (US) Committee on Toxicology. Nineteenth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington (DC): National Academies Press (US); 2011.

Cover of Nineteenth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A

Nineteenth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A.

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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 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.

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 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.

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. [PubMed: 12832658]
  • 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. [PubMed: 9441918]
  • 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. [PMC free article: PMC1007929] [PubMed: 3689720]
  • 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. [PubMed: 10698673]
  • 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. [PMC free article: PMC1008408] [PubMed: 698135]
  • 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. [PubMed: 12520073]
  • Willhite, C.C., V.H. Ferm, and R.P. Smith. 1981. Teratogenic effects of aliphatic nitriles. Teratology 23(3):17-23. [PubMed: 6266064]
  • 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. [PubMed: 18864097]
Copyright 2011 by the National Academy of Sciences. All rights reserved.
Bookshelf ID: NBK209433

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