IRIS Toxicological Review and Summary Documents for Acrolein (External Review Draft)
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The main metabolic pathway involves conjugation with glutathione, followed by excretion of mercapturic acid derivatives.
Acute exposures of humans suggest that the average threshold of sensation lies in the range of 0.09 (eye irritation) to 0.30 ppm (respiration rate, throat irritation) with nasal irritation at 0.15 ppm. No adaptation to these effects was observed. No chronic studies of humans exposed to acrolein are available. The only human study relating to cancer was a case control study in which there was a lack of a statistically significant increase in the cancer endpoints along with a likelihood of confounding concomitant exposure to other chemicals in the workplace.
No human studies are available regarding exposure by the oral route. In a 13-week gavage study, principal effects were forestomach and glandular stomach lesions in F344 rats and B6C3F1 mice with the NOAEL at 0.75 mg/kg (rats) with mortality in high-dose animals; there was no NOAEL for the mouse. However, 0.5 mg/kg was an FEL in a gavage study in the Sprague-Dawley rat; the cause is not readily apparent inasmuch as there was an absence of histopathological lesions. Thus, the study in in the Sprague-Dawley rat was selected as the principal study with 0.5 mg/kg/day as the FEL and 0.05 mg/kg/day as the NOAEL, based on mortality as the critical effect. Application of a total uncertainty factor of 100 to the NOAEL of 0.05 mg/kg/day gives the reference dose of 5 x 10-4 mg/kg/day.
No chronic inhalation studies involving human or laboratory animals are available. Exposure of Syrian golden hamsters, Wistar rats, and Dutch rabbits 30 hours/week for 90 days to 0, 0.4, 1.4, and 4.9 ppm (0.9, 3.2, and 9.2 mg/m3) acrolein resulted in mortality in rats at 4.9 ppm, while ocular and nasal irritation, growth depression and histopathologic changes in the respiratory tract were seen in all three species. At the intermediate dose, squamous metaplasia and neutrophilic infiltration of the nasal mucosa was seen in the rat, whereas in hamsters, minimal inflammatory changes were seen in the nasal cavity. No effects were detected in the nasal region in the mid and low-dose rabbits. Slight inflammatory effects were reported in the nasal mucosa of the rat, the most sensitive region at the lowest dose. The LOAEL for rats, the most sensitive species, is therefore 0.4 ppm for slight inflammatory changes of the nasal mucosa. The NOAEL for hamsters was determined to be 0.4 ppm and the LOAEL, 1.4 ppm, based on inflammatory changes in the nasal cavity. The NOAEL for rabbits was determined to be 1.4 ppm and the LOAEL 4.9 ppm. This study was selected as the most suitable study for derivation of the RfC. The critical endpoint is nasal histopathology (necrotizing rhinitis, keratinization, squamous metaplasia); nasal lesions appeared to be dose-related in severity (described as slight to severely affected) in all three species (rat, rabbit, and hamster). The LOAEL was duration-adjusted and adjusted to result in a Human Equivalent Concentration (HEC) to which a total uncertainty factor of 1,000 was applied to yield an RfC of 3 x 10-5 mg/m3. No uncertainty factor for the lack of adequate reproductive and developmental studies was adopted because (1) oral studies indicated that acrolein is unlikely to be a reproductive or teratogenic agent and (2) acrolein does not appear to cause effects beyond the point of contact.
In another study which exposed rats, guinea pigs, dogs, and monkeys 24 hours/day for 90 days to 0, 0.22, 1.0 and 1.8 ppm (0, 0.5, 2.3, and 4.1 mg/m3) acrolein suggested that 1 ppm may be a LOAEL because inflammation reported in several organs of one or more of the species. The principal deficiency in this study was the lack of use of concurrent control groups. In addition, it what not clear which changes were definitively related to exposure.
Applying the criteria outlined in the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986) for evaluating the overall weight-of-evidence for carcinogenicity to humans, acrolein is most appropriately designated a Group D-Inadequate Evidence for Carcinogenicity. Using the Draft Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1999), the data are inadequate for an assessment of the human carcinogenic potential. Two cancer bioassays failed to show an increase in tumor incidence when rats and mice were administered acrolein by gavage. Administration of acrolein in drinking water to female F344 rats resulted in an elevation of adrenocortical tumors over 104-124 weeks, but the increase was only significant when the tumors were combined with hyperplastic nodules. When the data were re-evaluated by an independent pathology working group (PWG) the tumors were considered to be well within limits for historical controls and were of no biological significance.
Two inhalation studies, one in hamsters and one in rats did not result in any carcinogenic response. However, the insufficient length and use of only one concentration in each study precluded any definitive conclusions about the carcinogenic potential of acrolein after inhalation.
Mutagenicity and genotoxicity studies provide little support to the possibility that acrolein may be carcinogenic. Although acrolein has been shown to be capable of inducing sister chromatid exchange, DNA crosslinking and mutations under certain conditions, its highly reactive nature and the lack of tumor induction at portals of entry make it unlikely that acrolein reaches systemic sites at biologically-significant exposure levels.
No information is available regarding early life susceptibility to acrolein.
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