Podophyllin office therapy against condyloma should be abandoned.

Podophyllin, a crude plant extract with low efficacy, high toxicity, and a serious mutagenicity profile does not comply with the WHO guidelines for plant derived treatments and should be removed from clinical treatment protocols. Home treatment with pharmaceutical products based on podophyllotoxin-the purified, standardised active antiwart ingredient of podophyllin-represents safe and effective first line therapy for patients with anogenital warts.

Condyloma eradication: self-therapy with 0.15-0.5% podophyllotoxin versus 20-25% podophyllin preparations--an integrated safety assessment.

Topical application of podophyllin solution, long considered the therapy of first choice against condylomata acuminata, can no longer be recommended due to its low efficacy and gross toxicity. Self-treatment with 0.15-0.5% purified podophyllotoxin preparations, applied twice daily for 3 days, is now advocated as the alternative first-line therapy of choice, when significant improvement is conveniently, and cost-effectively, accomplished within a few weeks. This review provides a summary of the comparative efficacy and utility of podophyllin versus podophyllotoxin as well as a compilation of in vivo and in vitro safety evaluations. In light of overwhelming safety and efficacy data in favor of podophyllotoxin-derived products, it is concluded that podophyllin preparations have no place in the modern treatment portfolio for anogenital warts.

Carcinogenic and mutagenic potential of several fluorocarbons.

A series of chlorofluorocarbons (CFC) have been evaluated for carcinogenic potential in two comprehensive toxicity studies. The first of these studies involved an assessment of their potential carcinogenicity using in vitro short-term predictive tests followed by a limited gavage validation assay in rats. The second study was a more conventional inhalation study of CFC22 employing rats and mice coupled with an assessment of in vivo genotoxicity of the material. The current paper briefly reviews these two studies and assesses the overall genotoxicity profile of CFC22 in terms of risk to man. It is concluded that CFCs are not biologically inert, but that the series contains bacterial mutagens, cell-transforming agents, and rodent carcinogens, and for this series of compounds at least, prokaryotic mutation does not accurately predict carcinogenic potential. In addition it is concluded that CFC22 does not represent a carcinogenic or mutagenic threat to man.

Activity of bromochlorodifluoromethane (BCF) in three mutation tests.

The halocarbon BCF was tested in 3 assays to assess its mutagenicity and clastogenicity. It produced a positive response in Salmonella typhimurium strain TA1535 but was negative in TA1537, TA1538, TA98 and TA100. In an L5178Y mouse lymphoma microwell assay (TK locus), BCF was negative. BCF was administered at 5000 and 50 000 ppm in air for 6 h to groups of C57B1/6J mice of both sexes. Animals were killed at 24, 48 and 72 h after cessation of exposure and the incidence of bone marrow micronuclei per 1000 PCEs determined. There was no significant difference in the incidences of micronuclei between untreated animals and those exposed to either concentration of BCF at any of the sampling times. These results suggest that BCF is mutagenic in vitro in only one strain of Salmonella; in mammalian cells the compound induced no gene mutation in vitro nor clastogenic activity in vivo at doses that also produced clear evidence of toxicity.

Genotoxicity and carcinogenicity of fluorocarbons: assessment by short-term in vitro tests and chronic exposure in rats.

Two short-term in vitro tests for mutagenicity (Salmonella reverse mutation and BHK21 cell transformation) were conducted on a series of fluorocarbons. Some of these materials (FC22, FC31, FC142b, FC143, and FC143a) were found to be positive in one or both of the tests and could therefore be considered as being potentially carcinogenic to animals. Such activity was not anticipated for what were previously considered inert materials and in consequence several examples of these fluorocarbons, which represented different combinations of short-term test results, were tested for carcinogenicity in limited in vivo bioassays. In these studies, rats were dosed for 1 year by gavage 5 days a week with either FC22, FC31, FC133a, FC134a, or FC143a dissolved in a corn-oil at a single dosage of 300 mg/kg body weight. The animals were then observed until week 125 with detailed necropsy at termination. The study revealed that FC31 was a potent carcinogen (to the rat stomach), a result which reflected the short-term test predictions, but FC133a, which gave a negative response in both the in vitro assays, induced a high incidence of reproductive tract tumors. The weak bacterial mutagens FC22 and FC143a did not induce tumors in this study, and the nonmutagenic FC134a was without overt carcinogenic activity. It is concluded that, while recognizing the limitations of the in vivo component of this study, the short-term tests were only partially successful in identifying potential carcinogens for this series of chemicals. Fluorocarbon 31 was a potent carcinogen which was first identified by bacterial mutation and cell transformation, whereas the equally potent carcinogen FC133a was not so identified. The lack of genotoxic activity with this particular compound leads us to believe that the carcinogenic activity may be due to mechanisms other than those which involve direct DNA interactions.

Nickel oxide: potential carcinogenicity--a review and further evidence.

A survey of the epidemiological and experimental evidence for nickel compound carcinogenesis suggests that nickel and nickel oxide should not be considered carcinogens for risk-assessment purposes. A rationalization of the observed experimental results from animal models using all exposure routes and based on differential solubilities in water and lipid has been proposed and explored in vitro with C3H10T1/2 cell-transformation studies. The results generated did not support this theory, but did support the argument that nickel and its oxide are noncarcinogenic. It is proposed that the IARC risk classification for nickel and nickel oxide should be modified accordingly.

Initiation/promotion versus complete carcinogenicity in the rodent liver.

4-N-Pyrrolidinylazobenzene (4N) is a close structural analog of the rodent liver carcinogen 4-dimethylaminoazobenzene (DAB). This structural similarity led us to evaluate it for genotoxic activity in vitro. We observed activity for 4N and DAB in the BHK cell transformation assay and subsequently in the Salmonella mutation assay of Ames. By a curious chance, Scribner, Miller and Miller, probably prompted by the same structural similarity, had synthesized 4N in the 1960s and found it to be noncarcinogenic to the rodent liver using a bioassay test protocol that detected DAB as carcinogenic. These findings were only described following the publication of our observations made in vitro. The conflict that apparently exists between these data can be interpreted in two separate ways. (a) Scribner et al. have suggested that 4N may be a carcinogenic initiator as opposed to a complete carcinogen like DAB. They also suggested that promotion of 4N-treated rodents with phenobarbitone might lead to the production of liver tumors. (b) We have evaluated the simpler concept that the activities observed for 4N in vitro define a carcinogenic potential that is not realized in vivo due to its rapid detoxification, at least in rodents. The first of these explanations implies that pure carcinogenic initiators may form a separate class of genotoxic agents from complete carcinogens, and perhaps of greater interest, that 4N might provide a valuable model compound for the study of carcinogenic promotion in the rodent liver. The second explanation regards potential carcinogenicity as a single property that can be defined in vitro and which may or may not be expressed in vivo depending on the enzymic environments encountered by the test chemical. It is clearly important to evaluate these different propositions in order to aid progress in the study of carcinogenic promotion, especially in the rodent liver. The presentation will describe our recent studies in vitro and in vivo in this connection.

Analysis of cell cultures of 3,4-benzpyrene-treated subcutis and subsequent growth in semi-solid medium.

An in vivo-in vitro implantation model has been used to investigate further the early stages of chemically induced s.c. neoplasia in the mouse. Cell cultures of implant-site tissues from control and 3,4-benzpyrene (BP)-treated animals were found to mirror the in vivo tissue reactions occurring at the time of explantation (Westwood et al., 1979). Cells were classified into 6 different types. The most abundant cell type in later control cultures was of a typical fibroblast morphology. However, a suppression of growth of fibroblast-like cells occurred when BP-treated tissues were explanted, and a selection of growth in favour of the large polygonal Type 5 cells was observed. When grown from BP-treated tissues Type 5 cells were found to be capable of growth in a semi-solid agar medium. Quantitative studies showed that cells capable of growth in agar reached a peak about 4 weeks after implantation, followed by a decline in numbers until the formation of tumours. This observation may result from the parameters regulating the development of chemically induced neoplasia in the subcutis.

Cellular progression of neoplasia in the subcutis of mice after implantation of 3,4-benzpyrene.

An implantation model has been used to investigate the cellular progression of chemically induced subcutaneous neoplasia in the mouse. Implantation of 3,4-benzpyrene induced persistent changes in the normal process of connective tissue formation around the implant. Light-microscope and autoradiographic studies have shown a temporal progression from aberrant filter- or muscle-associated cells through proliferative foci to large invasive sarcoma. Electron microscopy revealed that presarcomatous cell foci consisted of one of two different cell types. These were either spindle cells with ultrastructural characteristics similar to foreign-body-induced sarcoma, or cells with the ultrastructural features of rhabdomyosarcoma. The subsequent appearance of two histological groups of sarcoma that were ultrastructurally similar to the cells of the early proliferative foci indicated that both elements may progress to form tumours. However, the constituent cells of both groups of tumours displayed a broad histological and ultrastructural spectrum and the marked similarity between the undifferentiated cells of each suggested that both may have arisen from diverse differentiation of a common pluripotential cell such as the pericyte.

An evaluation of 6 short-term tests for detecting organic chemical carcinogens.

A number of tests have been described which are thought to be capable of identifying carcinogens without using the actual induction of cancer as an endpoint. This study compared the performance of 6 such tests on a selection of 120 organic chemicals. The tests studies were: (1) mutation of Salmonella typhimurium; (2) cell transformation; (3) degranulation of endoplasmic reticulum; (4) sebaceous gland suppression; (5) tetrazolium reduction and (6) subcutaneous implant. A further 4 tests were examined briefly, but were not included in the complete evaluation. The chemicals were classified into carcinogens (58) and non-carcinogens (62) on the basis of published experimental data, and into 1 of 4 broad chemical classes. There was considerable variation between tests in their ability to predict carcinogenicity, with the cell-transformation test and the bacterial-mutation test being the most accurate (94% and 93% accurate respectively). These 2 tests were considered to be of general use in screening, since they were clearly more accurate than the others. Statistical consideration of various combinations of these tests showed that the use of cell transformation and bacterial mutation together, provide an advantage over the use of either test alone. The inclusion of the other 4 tests in a screening battery predictably resulted in a great increase in overall inaccuracy and loss of discrimination, even though the detection of carcinogens is improved. All the tests were shown to generate both false positive and false negative results, a situation which may be controlled by the use, where possible, of appropriate chemical-class controls, to identify the test which is optimal for the class of chemical under test. Structural analogy may have a part to play in the rapid detection of environmental carcinogens, and some general guidelines for its use are given.