Mixed LOF

Specific investigations: other studies

Administrative data

Endpoint:

mechanistic studies

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

publication

Title:

Increased Frequency of Resistance to Terminal Differentiation in C3H Mouse Cells Produced by Genotoxic but Not Nongenotoxic Carcinogens

Author:

R. T. PRZYGODA, J. J. FREEMAN, S. KATZ and R. H. MCKEE

Year:

1994

Bibliographic source:

Toxicol. Sci. (1994) 23 (2): 261-267. doi: 10.1093/toxsci/23.2.261

Materials and methods

Principles of method if other than guideline:

Skin from mice treated with various petroleum products was evaluated in vitro to assess induction of terminal differentiation by calcium. Occurence of calcium resistant cells are believed to be represent early stages in the skin carcinogenesis process.

GLP compliance:

not specified

Type of method:

in vitro

Endpoint addressed:

carcinogenicity

Test material

Test material information

Constituent 1

Reference substance name:

Lightly refined paraffinic oil

IUPAC Name:

Lightly refined paraffinic oil

Details on test material:

Test material was a narrow cut, straight run middle distillate material which was refined by acid treatment. It contained approximately 16% aromatic constituents, the majority of which were one- to two-ring compounds. The only identified molecules containing more than two aromatic rings were
three-ring species, and these were not mutagenic when separated and tested in Salmonella assays. Repeated application to mouse skin produces tumors, but testing in two-stage carcinogenicity assays indicates the tumorgenic properties result from promotion, not initiation.

Test animals

Species:

mouse

Strain:

C3H

Sex:

male

Administration / exposure

Route of administration:

dermal

Vehicle:

unchanged (no vehicle)

Duration of treatment / exposure:

Single treatment

Doses / concentrations

Remarks:

Doses / Concentrations:
0.2 mL
Basis:
other: nominal amount applied

No. of animals per sex per dose:

Fourteen

Control animals:

yes, concurrent no treatment

yes, sham-exposed

Applicant's summary and conclusion

Conclusions:

Results indicate frequency of calcium resistant cells (keratinocytes) from the skin of mice treated with nongenotoxic petroleum substances such as lightly refined paraffinic oil or mineral oil are not greater than untreated or acetone-treated mice. Conversely, petroleum streams such as catalytically cracked clarified oil that are mutagenic in modified Ames assays are associated with significant increased frequency of calcium resistant cells in the skin of exposed mice. The results support the hypothesis that skin tumors resulting from repeated dermal exposure to irritating, but non-genotoxic petroleum streams are a secondary effect and not indicative of an inherent carcinogenic hazard property.

Executive summary:

Calcium-resistant cells (CRCs) may represent an early stage in the carcinogenic process, in part, because frequency increases after treatment with mutagens. The frequency of CRCs in C3H mouse skin was measured before and after treatment with certain petroleum-derived materials. Skin from mice treated with lightly refined paraffinic oil treatment did not significantly alter CRC frequency; however, treatment with genotoxic, carcinogenic catalytically cracked clarified oil resulted in a statistically significant and dose-related increase CRC in the skin from mice. These results are consistent with observations that genotoxic, petroleum-derived liquids are capable of tumor initiation in mouse skin, whereas petroleum derived materials which are not genotoxic do not initiate skin tumors. Thus, tumor production observed with these products is consistent with the hypothesis that repeated skin irritation or damage acts as a tumor promoting stimulus and is not the result of an inherently carcinogenic property.