Recent findings on the carcinogenicity of chlorinated olefins.

Data are presented on factors affecting the carcinogenic effects of chlorinated olefins, such as molecular structure, concentration, length of treatment, route of administration and animal species, strain, sex, and age. The observations are based upon carcinogenicity experimental bioassays of vinyl chloride and vinylidene chloride. Early results, which appear to show that some of these factors (particularly species, strain, and sex) act by affecting the metabolism of the tested compounds, are presented, and the need for metabolic characterization of experimental animals in chemical carcinogenesis is stressed.

A project of integrated research on the carcinogenicity of different halogenated and related compounds has been going on at the Bologna Institute of Oncology and Tumour Center since 1971, and additional programs in this area are under way or under study.
The experiments were performed by the same group in a very standard way, thus providing homogeneous and comparable information.
One is now becoming increasingly more aware that a great deal of this information may help not only to learn the effects of the particular compounds under study and their mechanism of action, but to better understand the basic factors involved in carcinogenesis in general.

Factors Affecting Neoplastic Response
The present report deals with the results obtained in our studies on the carcinogenicity of VC and VDC, pointing out the major factors affecting the neoplastic response.
The factors considered are: molecular structure, concentration, length of treatment, route of ad-*Institute of Oncology and Tumour Center, Bologna, Italy. ministration, animal species, strain, sex, age, and their relevance will be illustrated with VC and VDC.

Influence of the Molecular Structure
By comparing the carcinogenic activity of VC with that of VDC it can immediately be seen that molecules of very similar structure, such as vinyl chloride and vinylidene chloride, may have very different biological effects (Table 1).
While VC has been shown to affect many organs of different animal species, i.e., to be a clear multipotential carcinogen, VDC, to the present, has produced oncogenic effects definitively only in one organ (kidney) of a single species (mouse) (1-4).

Influence of Concentration
The studies on VC have already confirmed the dose-response relationship effect (1-3). Furthermore, they show that different concentrations, though within a narrow range of dose, may greatly affect the relative proportion of different types of tumors caused by VC (  greatly varies from species to species, though some, The schedule of treatment and especially the such as liver angiosarcomas, are observed in all length of administration, may also greatly affect the species tested (1-3). neoplastic response in VC carcinogenesis (Table 3).
Recent result with VDC (4) have pointed out that the only type of tumor known at present as definitively VDC-dependent, the renal adenocarcinoma, is observed in mice but not in the other two tested species, i.e., rats and Chinese hamsters, though rats have been treated with higher doses ( Table 5).

Influence of Strain
Differences have been observed among strain in VC carcinogenesis.
As an example, the onset of Zymbal gland carcinomas, following the treatment with this monomer, varies greatly in Sprague-Dawley and Wistar rats, though the spontaneous onset is exceptionally rare even in the most sensitive strain ( Table  6).

Influence of Sex
If VDC had been tested only on female Swiss mice, probably the knowledge of its capacity to produce kidney adenocarcinomas would not have come to light ( Table 7).

Influence of Age
Hepatocarcinogenesis by VC is a striking example of the influence of age in neoplastic response (Table 8).  However it becomes more and more evident that experimental and biological factors affecting the neoplastic response in chemical carcinogenesis as well as other possible toxic effects may act by determining the metabolic pathway of the tested compounds.
Recent research has shown that VC and VDC do not act per se, but through products of metabolic transformation, probably epoxy-derivatives.
Experiments performed in our laboratories appear to indicate that species, strain and sex greatly Explanation of Role of Factors affect the production of active metabolites, which in turn are responsible for toxic effects of VDC (Table  9) (5).

How the experimental and biological factors
The major regressive and necrotic changes prowhich have been considered and other possible duced by intoxication are found in liver and kidones determine the neoplastic response, is a matter neys.
of hypothesis and inference, more or less based In the case of Sprague-Dawley rats and Swiss upon experimental evidence. mice there is a clear cut parallelism between toxic To explain the influence of some biological and carcinogenic effects of VDC (in relation to parameters (such as species and strain), one has species and sex).
first to consider the genetic basis of responsive-As far as Balb/c, C3H, and C57BL mice are conness of different tissues and organs in various types cerned, we are now undertaking long-term studies of animals, often expressing itself in the onset of to assess if there is the same parallelism (in relation spontaneous neoplasia in the same tissue and organ. to strain). decrease; =, no change; +, enhancement (on 5th day). bCode:no effect; +, slight effect; + +, moderate effect; + + +, marked effect; + + + +, profound effect. Recovery has been observed on nearly all the survivors on the 5th day.

Environmental Health Perspectives
Should it be confirmed, we do believe that there will be new routes for establishing priorities for long-term carcinogenicity bioassays, for choosing the best experimental animal models and for the understanding of mechanism of action of many organic carcinogens.