Use of In Vivo and In Vitro Data to Derive a Chronic Reference Value for Crotonaldehyde Based on Relative Potency to Acrolein

Figures & data

TABLE 1. Physical Chemical Parameters for Acrolein and CRO

Parameter	Acrolein	CRO
Molecular formula	CH2 = CH—CHO	CH3-CH = CH–CHO
	(ATSDR 2007)	(ChemID Plus 2015)
Molecular weight (g/mol)	56.1	70.09
	(Texas Risk Reduction Program [TRRP] 2009)	(NRC 2007b)
Physical state	Liquid	Liquid
	(ATSDR 2007)	(NRC 2007b)
Odor	Disagreeable, choking odor, pungent	Strong, suffocating odor
	(ATSDR 2007)	(ATSDR 2002)
Solubility in water mg/L	121,000	181,000
	(ATSDR 2007)	(NRC 2007b)
Log Kow	−0.1	0.63
	(TRRP 2009)	(IPCS 2008)
Vapor Pressure	274 mm Hg	19 mm Hg (20°C)
	(ATSDR 2007)	(NRC 2007b)
Conversion Factors	1 ppm = 2.29 mg/m^3	1 ppm = 2.87 mg/m^3
	1 mg/m^3 = 0.44 ppm	1 mg/m^3 = 0.349 ppm
	(TCEQ 2014a)	(NRC 2007b)

FIGURE 1. Chemical structures for CRO (top) and acrolein (bottom).

TABLE 2. Comparison of Acute Sensory and Lethality Data

Test (Species)	Rank order	Value [ratio CRO to acrolein]	Reference
50% Odor detection threshold (humans)	Acrolein	8.2 μg/m^3 (3.6 ppb)	Nagata (2003)
	CRO	66 μg/m^3 (23 ppb)	Analytical concentrations
		[ratio 8.05]
RD50^a	Acrolein	6 ppm	Babiuk, Steinhagen, and Barrow (1985)^b
(male Fisher-344 rats)	CRO	23.2 ppm	Analytical concentrations
		[3.87]
RD50^a	Acrolein	1.41 ppm	Steinhagen and Barrow (1984)^b
(male B6C3F1 mice)	CRO	4.88 ppm	Analytical concentrations
		[ratio 3.46]
RD50^a	Acrolein	1.03 ppm	Steinhagen and Barrow (1984)^b
(male Swiss-Webster mice)	CRO	3.53 ppm	Analytical concentrations
		[ratio 3.43]
LC50, 30 min	Acrolein	0.3 mg/L (131 ppm)	Skog (1950)^b, c
(rat)	CRO	4 mg/L (1400 ppm)	Nominal concentrations^b
		[ratio 13.3]
LD50 subcutaneous injection^a	Acrolein	50 mg/kg	Skog (1950)^b
(rat)	CRO	140 mg/kg
		[ratio 2.80]
LD50 subcutaneous injection^a	Acrolein	30 mg/kg	Skog (1950)^b
(mouse)	CRO	160 mg/kg
		[ratio 5.33]

^aStudies that were used to calculate a CRO:acrolein RPF.

^bSee NRC (2007b) for details on the Babiuk, Steinhagen, and Barrow (1985), Steinhagen and Barrow (1984), and Skog (1950) studies.

^cSkog (1950) reported nominal concentrations, so a loss of CRO between the point of vapor generation and the animal breathing zone may have occurred at high concentrations, as discussed in Rinehart (1967).

TABLE 3. Acrolein and CRO Percent Viability Evaluated in NHLF Cells (MTT Test^a)

Concentrations	3 μM	10 μM	17 μM^b	30 μM	60 μM
Acrolein	97 ± 3	99 ± 3	91	76 ± 6	25 ± 2^c
CRO	99 ± 1	98 ± 1	—	94 ± 2	91 ± 2

^aMTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.

^bAs a sensitivity analysis, the estimated concentration corresponding to a 91% decrease in absorbance for acrolein was calculated. The concentration of 17 μM was calculated using a linear interpolation between 99% decrease in absorbance (10 μM) and 76% decrease in absorbance (30 μM).

^cStatistically different from control viability, p < .01.

TABLE 4. Comparison of IC₅₀ Values for Acrolein and CRO (3-h Exposure)

	IC50 viability (molar concentration)	IC50 ConA^a (molar concentration)	IC50 LPS^b (molar concentration)
Acrolein	2.70 × 10^−5	2.06 × 10^−5	3.16 × 10^−5
CRO	4.26 × 10^−5	2.01 × 10^−5	2.47 × 10^−5

^aConcanavalin A (ConA), a T-cell mitogen.

^bLipopolysaccharide (LPS), a B-cell mitogen.

TABLE 5. Comparison of Relevant Endpoints for Acrolein and CRO

Endpoint	Acrolein	CRO	Relative potency
RD50	6 ppm	23.2 ppm	3.87
Male Fisher-344 rats
Babiuk, Steinhagen, and Barrow (1985)
RD50	1.41 ppm	4.88 ppm	3.46
Male B6C3F1 mice
Steinhagen and Barrow (1984)
RD50	1.03 ppm	3.53 ppm	3.43
Male Swiss-Webster mice
Steinhagen and Barrow (1984)
LD50	50 mg/kg	140 mg/kg	2.80
Rat (subcutaneous injection)
LD50	30 mg/kg	160 mg/kg	5.33
Mouse (subcutaneous injection)
IC50 values for viability (in vitro) in mouse lymphocytes	2.70 × 10^−5 (molar concentrations)	4.26 × 10^−5 (molar concentrations)	1.58
Poirier et al. (2002).
Cell viability (in vitro) in cultured normal human lung fibroblasts	25	91	3.64
Moretto et al. (2009)

TABLE 6. Derivation of the Chronic ReV for CRO Based on Relative Potency

Chemical	Acrolein (TCEQ 2014b)^a
Parameter	Summary
Study	Dorman et al. 2008
Study population	360 adult Fischer-344 rats (12 rats/exposure concentration/time point)
Study quality	High
Exposure method	Discontinuous whole body at 0, 0.018, 0.052, 0.20, 0.586, or 1.733 ppm
Critical effects	Mild hyperplasia and lack of recovery of the respiratory epithelium
Exposure duration	6 h/d, 5 d/wk for 13 wk (65 d)
LOAEL	0.6 ppm
NOAEL	0.2 ppm
PODADJ	0.03571 ppm^b
PODHEC	0.03571 ppm^c
Total uncertainty factors (UFs)	30
Interspecies UF	3
Intraspecies UF	10
LOAEL UF	NA
Subchronic to chronic UF	1
Incomplete database UF	1
Database quality	High
Acrolein chronic ReV	1.2 ppb (2.7 μg/m^3)
RPF	CRO RPF = 3
CRO chronic ReV	3.6 ppb (10 μg/m^3)

^aSee Supplemental Material.

^bPODADJ = 0.2 ppm × 6 h/24h × 5d/7 d = 0.03571.

^cPOD_HEC = POD_ADJ × Regional Gas Dose Ratio (RGDR). The RGDR = 1 [dosimetric adjustments were performed as a Category 1 vapor in the extrathoracic region based on updated recommendations in U.S. EPA (2012)]. The PODHEC = 0.03571 ppm × 1 = 0.03571.

ChemIDPlus. 2015. A Toxnet database. http://chem.sis.nlm.nih.gov/chemidplus/ProxyServlet?chemidheavy ( accessed April 23, 2015).

 Google Scholar

Texas Risk Reduction Program. 2009. Chemical/physical properties table. http://www.tceq.state.tx.us/remediation/trrp/trrppcls.html ( accessed April 25, 2013).

 Google Scholar

National Research Council. 2007b. Crotonaldehyde, trans and cis + trans. National Research Council. Acute exposure guideline levels for selected airborne chemicals. In Committee on Acute Exposure Guideline Levels, Committee on Toxicology, vol. 6. 123–72. Washington DC: The National Academy Press

 Google Scholar

Agency for Toxic Substances and Disease Registry. 2007. Toxicological profile for acrolein. U.S. Department of Health and Human Services. http://www.atsdr.cdc.gov/toxprofiles/tp124.pdf ( accessed April 25, 2013).

 Google Scholar

Agency for Toxic Substances and Disease Registry. 2002. ToxFAQs™ for crotonaldehyde. http://www.atsdr.cdc.gov/toxfaqs/tf.asp?id=948&tid=197 ( accessed April 25, 2013).

 Google Scholar

International Programme on Chemical Safety. 2008. Concise international chemical assessment document 74. Geneva, Switzerland: World Health Organization. http://www.who.int/ipcs/publications/cicad/cicad74.pdf ( accessed March 26, 2013).

 Google Scholar

Texas Commission on Environmental Quality. 2014a. Development support document: Crotonaldehyde (Cis and Trans), CAS registry number: 4170-30-3 Trans-Crotonaldehdye, CAS registry number: 123-73-9; Cis-Crotonaldehyde, CAS registry number: 15798-64-8. Toxicology Division, Office of the Executive Director. http://www.tceq.state.tx.us/implementation/tox/dsd/final.html

 Google Scholar

Nagata, Y. 2003. Measurement of odor threshold by triangle odor bag method. Odor Measurement Review, 118–27. Japan Ministry of the Environment. http://www.env.go.jp/en/air/odor/measure/02_3_2.pdf ( accessed July 22, 2015).

 Google Scholar

Babiuk, C., W. H. Steinhagen, and C. S. Barrow. 1985. Sensory irritation response to inhaled aldehydes after formaldehyde pretreatment. Toxicology and Applied Pharmacology 79:143–49. doi:10.1016/0041-008X(85)90376-X.

 PubMed Web of Science ®Google Scholar

Steinhagen, W. H., and C. S. Barrow. 1984. Sensory irritation structure–activity study of inhaled aldehydes in B6C3F1 and Swiss-Webster mice. Toxicology and Applied Pharmacology 72:495–503. doi:10.1016/0041-008X(84)90126-1.

 PubMed Web of Science ®Google Scholar

Skog, E. 1950. A toxicological investigation of lower aliphatic aldehydes: I. Toxicity of formaldehyde, acetaldehyde; propionaldehyde and butyraldehyde; as well as of acrolein and crotonaldehyde. Acta Pharmacologica et Toxicologica 6:299–318. doi:10.1111/(ISSN)1600-0773.

 PubMedGoogle Scholar

Rinehart, W. E. 1967. The effect on rats of single exposures to crotonaldehyde vapor. American Industrial Hygiene Association Journal 28:561–66. doi:10.1080/00028896709342685.

 PubMed Web of Science ®Google Scholar

Poirier, M., M. Fournier, P. Brousseau, and A. Morin. 2002. Effects of volatile aromatics, aldehydes, and phenols in tobacco smoke on viability and proliferation of mouse lymphocytes. Journal of Toxicology and Environmental Health, Part A 65:1437–51. doi:10.1080/00984100290071342.

 PubMed Web of Science ®Google Scholar

Moretto, N., F. Facchinetti, T. Southworth, M. Civelli, D. Singh, and R. Patacchini. 2009. α,β-Unsaturated aldehydes contained in cigarette smoke elicit IL-8 release in pulmonary cells through mitogen-activated protein kinases. AJP: Lung Cellular and Molecular Physiology 296:L839–L848. doi:10.1152/ajplung.90570.2008.

 Google Scholar

Texas Commission on Environmental Quality. 2014b. Development support document: Acrolein, CAS registry number: 107-02-8. Toxicology Division, Office of the Executive Director. http://www.tceq.state.tx.us/implementation/tox/dsd/final.html

 Google Scholar

Dorman, D. C., M. F. Struve, B. A. Wong, M. W. Marshall, E. A. Gross, and G. A. Willson. 2008. Respiratory tract responses in male rats following subchronic acrolein inhalation. Inhalation Toxicology 20:205–16. doi:10.1080/08958370701864151.

 PubMed Web of Science ®Google Scholar

U.S. Environmental Protection Agency. 2012. Advances in inhalation gas dosimetry for derivation of a reference concentration (RfC) and use in risk assessment. EPA/600/R-12/044. Washington, DC: U.S. Environmental Protection Agency.

 Google Scholar