Tenth Interim Report of the Subcommittee on Acute Exposure Guideline Levels (2004)

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TENTH INTERIM REPORT OF THE SUBCOMMITTEE ON ACUTE EXPOSURE GUIDELINE LEVELS 8 Specific Comments Page 1, line 15. Change tense to “produced” from “will be produced.” Table 20–22. These tables should be deleted. They are likely to confuse the reader and are unnecessary. Page 28, lines 15–18. It should be pointed out here that PO reacts with glutathione (GSH) enzymatically (via GSH S-transferase) and non-enzymatically as well. It should also be pointed out that these reactions represent detoxification pathways, as PO is a direct alkylating agent. Page 29, lines 20–39. Have the toxicokinetic data described here been published in the peer-reviewed literature? Such information is pertinent to the conclusion (lines 1–3 of page 33) that species differences in susceptibility to PO are quite modest. Page 31, lines 2–19. Additional information should be provided on potential mechanism(s) of PO-induced preneoplastic changes and carcinogenicity in the respiratory tract. Rios-Blanco et al. (2003a, b), as described later in this critique, recently reported dose-dependent cellular proliferation and DNA binding in the nasal epithelium of rats inhaling a series of concentrations of PO over periods of 3 and 20 days. These publications resulted from work conducted as part of a robust, ongoing research program focusing on the mechanism of PO carcinogenicity in the rat. Page 33, lines 1–2: The introductory sentence is vague and should be modified to clarify that mice are the most susceptible species to acute lethality, but that mice, rats, dogs and humans may not differ by more than 3.5- fold in sensitivity to systemic effects (effects undefined, as there is little evidence of adverse effects other than those at the portal of entry). Swenberg and Filser (1998) predict a higher steady-state blood level and a longer t1/2 for PO in humans than in mice and rats. Page 34, lines 7–35. The authors of this document should consider using findings reported by CMA (1998a) as the basis for derivation of AEGL-1 values for PO. The eye irritation described by this group is an appropriate end point for AEGL-1. However, time scaling should not be performed for minor/modest mucus membrane irritation associated with PO exposures. Page 37, lines 1–25. As the observations in the CMA (1998a) report are appropriate for AEGL-1, data on more severe irritation, port of entry cytotoxicity, and/or systemic toxicity are needed to derive AEGL-2 values. There is very little relevant information for these end points in the current AEGL document. PO does not produce neurotoxically in monkeys or rats or recognizable histopathological changes. Swenberg and co- workers, however, recently published a well-conducted study that resulted in findings more applicable to AEGL-2. Rios-Blanco et al. (2003a) assessed histological changes and cellular 

TENTH INTERIM REPORT OF THE SUBCOMMITTEE ON ACUTE EXPOSURE GUIDELINE LEVELS 9 proliferation in nasal and hepatic tissues of groups of male F344 rats exposed to a series of concentrations of PO vapor 6-hr daily over intervals of 3 and 20 days. It is noteworthy that no exposure-related changes in cellular proliferation were observed in the liver. The transitional epithelium of the anterior nasal passages showed the most pronounced changes in the target tissue, and it is noteworthy that the nasal tumors described in previous studies occurred in this region. Vapor concentration-dependent increases in cellular proliferation occurred in the same site in the rats that inhaled 300 or 500 ppm for 3 days. No such changes were manifest at 50 ppm. Alternatively, the NOAELs/LOAELs for histopathological changes following inhaled PO could be utilized to calculate AEGL-2 values. The ten Berge (1986) approach to time-scaling may not be appropriate for the portal-of-entry effects seen by Rios-Blanco et al. (2003a). The extent of nasal epithelial proliferation observed was no more serious after 20 days than after 3 days of their exposure regimen. Maples and Dahl (1993) (lines 5–8, page 29) found that circulating PO levels plateaued after the first 10-min of a 1-hr inhalation exposure of rats at 14 ppm. The severity of the aforementioned changes was quite modest, though cytotoxicity and compensatory cellular proliferation may very well be pertinent to the mechanism(s) of carcinogenicity of PO similar to that seen after inhaled formaldehyde, hydrazine, and other highly reactive gases. Accordingly, uncertainty and modifying factors (if required at all) for AEGL-2 derivation should be modest. Rios-Blanco et al. (2003b) reported finding DNA binding, an even more sensitive index of PO exposure, in a second recent publication. DNA binding was measured in the nasal epithelium, lung, and liver of the same groups of rats utilized for the Rios-Blanco et al. (2003a) publication, and N7-(2-hydroxypropyl) guanine formation was greatest in the nasal epithelium. Levels of the DNA adduct in the nasal epithelium after 3 daily 6-hr exposures increased linearly with the inhaled concentration. The binding of DNA at the target tissue at 5 ppm, the lowest concentration studied, should be pointed out. Page 37, lines 32–34. See comments previously (p. 33, lines 1 and 2) made about clarifying anticipated similarities in susceptibility of different species to PO toxicity. Page 39, lines 4–25. A mouse or rat LC50 value should be used as the basis for derivation of AEGL-3. Page 43, lines 22–36. It should be pointed out here that there is a paucity of data relevant to derivation AEGL-1 and -2. This section should be used to describe what data are needed, rather than to reiterate and rationalize the selection of AEGL calculations. Page 50. The key question in this section is whether cancer could result in human beings after a single 10-min to 8-hr inhalation exposure to PO. Sellakumar et al. (1987) demonstrated that repeated PO exposures of male Sprague-Dawley rats over periods of 8 or 30 days failed to elicit any evidence of carcinogenicity. These findings and their cancer risk implications of acute PO exposure should be the first topic addressed in this section.