Animal studies lifetime bioassays

Just within the past decade have definitive animal studies for arsenic-induced carcinogenesis emerged with positive results (Kitchin, 2001 Hughes, 2002 Rossman, 2003 Wanibuchi et al., 2004 Cohen et al., 2006 Waalkes, Liu and Diwan, 2007). Up until this point, standard lifetime cancer bioassays with inorganic... 

The Subcommittee on Permissible Exposure Levels for Military Fuels also discussed animal studies of chronic inhalation exposures to JP-4 and unleaded-gasoline vapor studies of subchronic inhalation exposures to JP-8, JP-5, and JP-4 and studies of dermal exposure (skin painting) to JP-5 and DFM (NRC 1996). No lifetime inhalation animal bioassays of JP-5, JP-8, or DFM were located. Among the studies discussed in the 1996 report, the subchronic inhalation studies ofJP-8 (Mattie etal. 1991) and the studies ofJP-5 (Gaworski et al. 1984, 1985 NTP 1986) and JP-4 (Bruner et al. 1993) are the most relevant to the present assessment. Those studies are discussed below with additional studies included in the current assessment. 

An NCI bioassay (NCI 1978) administered time-weighted average (TWA) doses of 1.6-5 ppm endrin in feed to B6C3Fj mice and 2.5-6 ppm in feed to Osbome-Mendel rats for 80 weeks. No significantly increased incidence of tumors in treated animals was reported, but the study is limited by the less-than-lifetime dosing regime. 

Furnace oil (CAS no. 68474-30-2) was evaluated for skin carcinogenicity with both lifetime skin-painting and an initiation/promotion bioassay (Gerhart et al. 1988). Briefly, in the lifetime skin-painting study, 50 microliters of undiluted furnace oil was applied to 50 male C3H/HeN mice twice weekly for the lifetime of the animals. A sham negative control group of equal size was ran concomitantly. In the initiation portion of the initiation/promotion bioassay, 30 CD-I mice received five treatments of 25 microliters or five treatments of 50 microliters of furnace oil, and both groups were subsequently treated with 50 microliters of 0.1 mg/mL phorbol-12-myristate-13-acetate (PMA) twice weekly for 25 weeks. Thirty mice received... 

Lifetime cancer bioassays using orally exposed animals were not located. In a shorter-term study, exposure to p-cresol in the feed for 20 weeks produced an increased incidence of forestomach hyperplasia in hamsters, suggesting that this cresol isomer may have the potential to act as a promoter of forestomach carcinogenesis in this species (Hirose et al. 1986). However, promotion potential was not tested directly. p-Cresol did not produce forestomach hyperplasia in rats (Altmann et al. 1986), but rats are generally less sensitive than hamsters to inducers of forestomach lesions. 

Chronic studies are typically conducted for periods 90 days and usually up to the length of the lifetime of the test animal. In some cases, as with bioassays for carcinogenesis, the animals are exposed daily for their lifetimes (usually 18 months in mice and 2 years in rats). Chronic studies focus on identifying effects (e.g., such as cancer or certain reproductive effects) that might occur following continuous exposure over several generations. 

No studies were loeated examining potential relationships between skin eancer in humans and dermal exposure to formaldehyde, but two mouse-skin cancer bioassays found no evidence for increased incidence of skin tumors after 58-60 weeks of twice-weekly exposure to formaldehyde solutions at concentrations of 4% (Iverson 1988) and 10% (Iverson 1986). Additional animal bioassays employing lifetime dermal exposure scenarios would provide more complete assessments of the possible dermal carcinogenicity of formaldehyde. 

The lifetime carcinogenicity of JP-8 has not been studied therefore, the subcommittee recommends that 2-yr inhalation carcinogenicity bioassays be conducted in two experimental animal species. 

Other jet fuels have not been tested in lifetime rodent carcinogenicity bioassays by the inhalation route, but 12-mo exposure studies of JP-4 and 90-day continuous-exposure studies of JP-5 discussed in the 1996 National Research Council report are briefly described here. Bruner etal. (1993) exposed groups of 100 F344 rats of each gender and 100 C57B1/6 mice of each gender to JP-4 at 1,000 or 5,000 mg/m3 for 6 hr/day, 5 days/wk for 12 mo animals were allowed to live unexposed for an additional 12 mo. In rats, an increase in renal-cell tumors (three renal-cell adenomas, one carcinoma, and one sar-... 

As summarized by Nessel (1 999), middle distillate fractions (MDFs) have been tested in numerous lifetime mouse skin-painting studies over the last 20 yr. Early mouse skin-painting studies documenting the carcinogenicity of MDFs in mouse skin include those of Lewis et al. (1984) and Biles et al. (1988), as cited by Nessel (1999). MD API 81 -07, a hydrodesulfurized kerosene, was also shown to induce skin tumors in a C3H/HeJ mouse skin-painting 2-yr bioassay in 50% of the animals with a tumor latency of 76 wk (API 1988, as cited by Skisak 1991). 

The subcommittee concludes that the available data are insufficient to draw a conclusion regarding the carcinogenicity of inhaled JP-8. However, because some studies show that chronic dermal exposure to high doses of jet fuels or other petroleum products produces skin tumors, the subcommittee recommends that the Department of Defense (DOD) conduct lifetime carcinogenicity bioassays by the inhalation route in two animal species to determine whether JP-8 is carcinogenic via inhalation. The subcommittee also recommends that DOD follow a cohort of military personnel (including obtaining their exposure history) to determine whether exposure to JP-8 is associated with an increased incidence of various types of cancers. 

Application of this 1/100 safety factor to the NOAEL (1 ng/kg/day or 1000 pg/kg/day) defined in the lifetime rat study (30) that is considered most definitive by essentially all of the regulatory agencies was the basis for the Ontario MOE expert panel to recommend a Maximum Daily Intake for 2,3,7,8-TCDD (or its toxic equivalent of other chlorinated dioxins and furans) of 10 pg/kg B.W./day for humans (38). This more recent approach used by these four non-U.S. groups demonstrate the manner in which carcinogenicits based lifetime exposure control limit recommendations for humans can be realistically derived from the data available from the animal cancer bioassays when interpreted in concert with the data available regarding the likely mechanism of action by which the carcinogenic response occurred in the animal bioassays. 

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