Analysis of chloroethane toxicity and carcinogenicity including a comparison with bromoethane

Abstract

Chloroethane (CE) gas carcinogenicity is analyzed and determined from a National Toxicology Program (NTP) bioassay where an inhalation concentration of 15,000 ppm CE gas in air produced the highest incidence of an uncommon-to-rare tumor ever observed by the NTP. Persistently inhaled CE produces endometrial cancers in female mice. The first-tumor-corrected uterine endometrial incidence (I) in B6C3F1 mice is 90%, but no significant tumors occurred in F344 rats. The endometrial cancers dispersed by 1) migrating locally to the adjacent myometrium, 2) then migrating to the bloodstream by intravasation, 3) entering 17 distal organs by extravasation and adapting to the new tissue environment. Distal cancers retained sufficient endometrial cell features to be recognized at each metastatic site. CE produced one of the highest metastasis rates ever observed by NTP of 79%. Comparing CE with bromoethane (BE), a structural analogue, it was found that BE too produced rare murine endometrial cancers yielding the second highest NTP incidence rate of I = 58% with a similar high malignancy rate of 56%. Because of the historical rarity of endometrial tumors in the B6C3F1 mouse, both of these SAR haloethanes seem to be evoking a strong, related carcinogenic potential in B6C3F1 mice, but not in F344 rats. The question of whether humans are similar to mice or to rats is addressed here and in Gargas, et al., 2008. The powerful carcinogenesis caused by these halohydrocarbons may have been caused by excessive and metabolically unresolved acetaldehyde (AC) which is directly generated by Cyp2E1 in the oxidative elimination of CE. With >95% AC metabolic production, as predicted from pharmacokinetic (PK) studies depending on CE exposure, AC is the main elimination intermediate. AC is a known animal carcinogen and a strongly suspected human carcinogen. Also, CE causes incipient decreases of tissue essential glutathione pools [GSH] by Phase II conjugation metabolic elimination of CE (and BE), by glutantione transferase (GST), in most organs (except brain) exposed to high circulating CE and it metabolites. In three laboratories, an excessive stress reaction of hyperkinesis was observed only during 15,000 ppm gas exposure but not when the exposure ceased or when exposure was presented at 150 ppm. Test rodents other than the female mice did not exhibit a pattern of visible stress nor did they have a carcinogenic response to CE gas. Unremitting stress has been documented to contribute a feedback to the hypothalamus which stimulates the hypothalamic-pituitary-axis (HPA), which in turn, induces the adrenal glands. Because estrus and estrogen and progesterone levels were unaltered by CE gas, the adrenal over stimulation, causing high steroid output, may be the penultimate step in this extraordinary carcinogenic response. High adrenal production of corticosteroids could adversely promote endometrial cells to cancers in mice - a mechanism that has already been observed in humans.

Headspace-Free Setup of in Vitro Bioassays for the Evaluation of Volatile Disinfection By-Products

“…Bromoform had been reported earlier as umuC-positive, which was confirmed by our findings. Bromoethane was reported as Ames positive in the TA100 strain in a previous study, which applied the agar-plate version of the Ames assay in a vapor exposure unit to avoid the loss of volatiles, and was shown to be carcinogenic in an inhalation-exposure study with mice . Dichloromethane was reported as weakly Ames positive in the TA100 strain with metabolic activation using a preincubation procedure to minimize the loss of volatile test chemicals and with or without S9 using a gas exposure unit .…”

Genotoxic Impurities: From Structural Alerts to Qualification

“…Rodent bioassay data on alkyl halides (Table ) strongly suggest that these compounds are either noncarcinogens (1-chlorobutane, bromomethane) or low-potency carcinogens (chloroethane, bromoethane). Both chloroethane and bromoethane produced an increased incidence of a rare type of endometrial tumour in female mice and it seems highly plausible that the carcinogenic effect is caused by a species-/gender-specific stress-related adrenal overstimulation and excessive corticosteroid production. The rodent carcinogenicity profile for chloroethane (increased incidence of a rare tumour type at an extremely high concentration of 15,000 ppm in one species/gender) is thus much closer to that for a nongenotoxic carcinogen than for a genotoxic carcinogen.…”

Manufacture of the PI3K β-Sparing Inhibitor Taselisib. Part 2: Development of a Highly Efficient and Regioselective Late-Stage Process

“…For these reasons, aqueous washes with water and 13 wt % NaCl solution prior to acidification were implemented to remove the residual KF salt. Finally, acidification was performed with HCl in 1-propanol instead of ethanol to avoid the formation of the potential mutagenic impurity EtCl …”

“…Finally, acidification was performed with HCl in 1-propanol instead of ethanol to avoid the formation of the potential mutagenic impurity EtCl. 7 Next, we turned our attention to the development of the key intramolecular cyclization to form the benzoxazepine ring system. We attempted to initiate this cyclization from 7•HCl with catalytic protic acids and bases; however, no product was observed until we switched to a Lewis acidic system (Table 1).…”