Skin-painting studies

Section 8 of TSCA has made EPA and the industry aware of nitrosamine contamination in metalworking fluids. In one particular potentially significant notice of substantial risk (8E-1077-0 012), skin painting studies showed an increase above the expected normalincidence of tumors in the livers and lungs of mice with no unusual incidence of skin tumors. Due to the similarity between the observed effects and the mechanism of action of nitrosamines (i.e., the apparent systemic effect of the substance and organ specificity of the tumors), the company attributed the response to a nitrosamine contaminant in the fluid. 

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... 

In a 2-year skin-painting study designed to evaluate the role of skin irritation in the tumorigenicity of middle distillates, 37.5 microliters of jet fuel and steam cracked gas oil were applied two times per week, and jet fuel was also applied in an intermittent fashion (dosing was suspended when irritation was noted in 20% of the group and resumed when it was resolved in all but 20%) (Freeman et al. 1993). Intermittent... 

EPA. 1983. Summary of preliminary results from lifetime skin-painting study. TSCA Chem-in-Prog Bull 4 3 10 May 1983. Environmental Protection Agency. Washington DC. 

Acetone may be weakly genotoxic, but the majority of assays were negative. It was not tumorigenic in skin painting studies in mice. 

In mice skin-painting studies, skin tumors were produced by steam-refined petroleum bitumens, an air-refined bitumen in toluene, two cracking residue bimmens, and a pooled mixmre of steam- and air-blown petroleum bitumens. In contrast, standard roofing petroleum asphalts produced no tumors. 

Toxicology. Catechol is a skin, eye, and respiratory tract irritant and at high concentrations may cause convulsions it acts as a cocarcinogen in animal skin-painting studies and produces stomach mmors after oral administration in rodents. 

In skin-painting studies in mice, catechol increased the carcinogenic effects of benzo[< ]pyrene (B(skin tumors was compared with that obtained from groups treated with B([Pg.129]

Pellets of cholesterol containing 2 mg of hydroquinone implanted in mice bladders caused an excessive number of bladder carcinomas. hr other studies, rats fed up to 1% hydroquinone in their diets for 2 years did not develop tumors, nor did hydroquinone initiate significant numbers of tumors in mice skin painting studies. ... 

Thiram also was not carcinogenic in rats by gavage or in mice by single subcutaneous injection. " In skin painting studies in mice thiram had tumor-initiating and -promoting activity but was not a complete carcinogen. ... 

United States National Toxicology Program (1996) Comparative Initiation/Promotion Skin Paint Studies ofB6C3Fi Mice, Swiss (CD-I ) Mice, and Senear Mice (Tech. Rep. Ser. No. 441 NIH Publ. No. 96-3357). Research Triangle Park, NC... 

In skin painting studies in mice, catechol increased the carcinogenic effects of benzo [a]pyrene on the skin (lARC, 1977). 

Toluene was tested for carcinogenicity in one strain of rats by gavage at one dose level and in one strain of rats by inhalation. These studies were inadequate for evaluation. Toluene was used as a vehicle control in a number of skin-painting studies. Some of these studies were inadequate for evaluation. In others, repeated application of toluene to the skin of mice did not result in an increased incidence of skin tumours (lARC, 1989a). 

Vinylidene chloride was tested for carcinogenicity in mice and rats by oral administration and inhalation exposure, in mice by subcutaneous administration and topical application and in hamsters by inhalation. Studies in mice and rats by oral administration gave negative results. In inhalation studies, no treatment-related neoplasm was observed in rats or hamsters. In mice, treatment-related increases in the incidence of kidney adenocarcinomas were observed in male mice, as were increases in mammary carcinomas in females and pulmonary adenomas in male and female mice. In skin-painting studies in female mice, vinylidene chloride showed activity as an initiator, but in a study of repeated skin application, no skin tumour occurred. No tumour at the injection site was seen in mice given repeated subcutaneous administration. 

Limited information is available regarding the health effects of barium following dermal exposure. Barium salts would be expected to have a local effect on skin surfaces and would not likely be absorbed systematically to any great extent. Available studies include a case report of an individual exposed dermally to molten barium chloride (Stewart and Hummel 1984), a skin irritation study evaluating barium carbonate in experimental animals (Tarasenko et al. 1977), and a skin-painting study in which mice were exposed dermally to a barium hydroxide extract of tobacco leaf (Van Duuren et al. 1968). No reliable information was available from any of these dermal studies to identify study NOAELs or LOAELs for barium. In the case report (Stewart and Hummel 1984), the dermal burns that developed in the individual exposed to molten barium chloride may potentially have contributed to some of the reported health effects, which are described briefly in Section 2.2.3.2 (Systemic Effects). 

No studies were located regarding cancer in animals after dermal exposure to barium. However, results of one skin-painting study with mice suggest that barium hydroxide extract derived from tobacco leaf may act as a tumor-promoting agent (Van Duuren et al. 1968). In this study, mice were treated dermally for an unspecified period of time with either barium hydroxide extract alone, 7,12-... 

Results of one skin-painting study with mice suggest that barium hydroxide extract derived from... 

Cancer. No studies were located regarding the carcinogenic potential of 2-nitrophenol or 4-nitrophenol in humans by any route of exposure or in animals by the inhalation or oral route. Neither isomer induced tumors when applied to the backs of mice in doses of 47 mg/kg/day for 12 weeks (Boutwell and Bosch 1959). However, since no other site was examined and the duration of the study was only 12 weeks, the results should be interpreted with caution. The relevance of this information to human health is unknown. NTP (1991) recently conducted a review of a 2-year skin painting study with 4-nitrophenol in mice. The panel concluded that under the conditions of the study, there was no evidence of carcinogenic activity in male or female Swiss-Webster mice receiving doses of up to 160 mg 4-nitrophenol/kg for 78 weeks. 

Dibenz[d, /i]anthracene is a confirmed animal carcinogen. It produced carcinomas in mice both via dermal and oral routes of administration. Skin painting studies have produced mammary tumors. Lung... 

No studies were located regarding cancer in animals after inhalation or oral exposure to any isomer of DNP. Two skin painting studies in female mice using DMBA as an initiator reported that 2,4- DNP... 

Jet fuels other than JP-8 have been tested for carcinogenicity in animal studies by the dermal route. In addition to the skin-painting studies of JP-5 by the National Toxicology Program (NTP 1986) discussed in the 1996 NRC report, studies of jet fuel A (Clark et al. 1988 Freeman et al. 1993) and JP-4 (Clark et al. 1988) are described here. 

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 role of skin irritation in the development of skin tumors was investigated by Nessel et al. (1998). In lifetime C3F1 mouse skin-painting studies, MDFs, including a straight-run kerosene, were applied neat and in 50% and 28.6% dilutions. Treatment with the neat straight-run kerosene induced skin tumors and skin irritation treatment with the diluted material produced neither... 

Although they did not catalog their bioassay findings from the alkane-B[fl]P experiments in their extensive tabnlation of the induction of carcinoma in skin-painting studies with tobacco products [see pp. 330-331 in (4319) and pp. 370-371 in (4332)], Wynder and Hoffmann offered the following explanation for the result observed ... 

Consideration of all the tumorigenic PAHs and their levels in CSC could account for no more than 3% of the observed biological activity in mouse skin-painting studies. In 1961, Wynder and Hoffmann (4312) stated ... 

Although most of the past theories have attempted to define the relationship between structural properties of the PAHs and their specific tumorigenicity as measured individually in skin-painting studies, little has been done to explain the behavior of a PAH when it is present in a complex mixture that includes a host of PAHs some of which are known antitumorigens as well as numerous known non-PAH antitu-morigens (1174). 

Subsequent to the publication of the Preussmann and Stewart review (2991), Deutsch-Wenzel et al. (956a) reported that in a skin-painting study with N -nitrosonornicotine (NNN), tumors were initiated at the site of application. The specific tumorigenic potency of NNN was estimated to be only 0.8% of that of B[a]P. However, no dose response relationship was observed with NNN over a treatment range of 12.5 to 200 pg. 

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