Use of the benchmark‐dose (BMD) approach to derive occupational exposure limits (OELs) for genotoxic carcinogens: N‐nitrosamines

Abstract

N-Nitrosamines are potent carcinogens and considered non-threshold carcinogens in various regulatory domains. However, recent data indicate the existence of a threshold for genotoxicity, which can be adequately demonstrated. This aspect has a critical impact on selecting the methodology that is applied to derive occupational exposure limits (OELs). OELs are used to protect workers potentially exposed to various chemicals by supporting the selection of appropriate control measures and ultimately reducing the risk of occupational cancer. Occupational exposures to nitrosamines occur during manufacturing processes, mainly in the rubber and chemical industry.The present study derives OELs for inhaled N-nitrosamines, employing the benchmark dose (BMD) approach if data are adequate and read-across for nitrosamines without adequate data. Additionally, benchmark dose lower confidence limit (BMDL) is preferred and more suitable point-of-departure (PoD) to calculate human health guidance values, including OEL. The lowest OEL (0.2 μg/m 3 ) was derived for nitrosodiethylamine (NDEA), and nitrosopiperidine (NPIP) (OEL = 0.2 μg/m 3 ), followed by nitrosopyrrolidine (NPYR) (0.4 μg/m 3 ), nitrosodimethylamine (NDMA), nitrosodimethylamine (NMEA), and nitrosodipropylamine (NDPA) (0.5 μg/m 3 ), nitrosomorpholine (NMOR) (OEL = 1 μg/m 3 ), and nitrosodibutylamine (NDBA) (OEL = 2.5 μg/m 3 ).Limits based on "non-threshold" TD50 slope calculation were within a 10-fold range. These proposed OELs do not consider skin absorption of nitrosamines, which is also a possible route of entry into the body, nor oral or other environmental sources. Furthermore, we recommend setting a limit for total nitrosamines based on the occupational exposure scenario and potency of components.

Benchmark dose determining airborne crystalline silica particles based on A549 lung-cell line survival in an in vitro study

“…F1 (Intra-species variation): based on the assumption that the variability in the general population, including children, the elderly, and diseased individuals, is higher than in workers, A default value of 5 for workers was applied (31,32).…”

“…F2 (LOAEL to NOAEL extrapolation): the BMDL10 is considered a LOAEL since the biological effect was a 10% increase in cancer incidence. A maximum factor of 10 is used when deriving an OEL from a LOAEL, instead of a NOAEL (31).…”