No abstract

Vinyl chloride (VC) is both a known carcinogen and a regulated chemical, and its production capacity has almost doubled over the ltst 20 years, currently 27 million tons/year woddwide.According to recent reports it is still a cause for concern. VC has been found as degradaton product of chloroethylene soIvents (perchloroethylene and trichloroethylene) and in landfill gas

Vinyl chloride (VC) is both a known carcinogen and a regulated chemical, and its production capacity has almost doubled over the last 20 years, currently 27 million tons/year worldwide. According to recent reports it is still a cause for concern. VC has been found as a degradation product of chloroethylene solvents (perchloroethylene and trichloroethylene) and in landfill gas and groundwater at concentrations up to 200 mg/m(3) and 10 mg/L, respectively. Worldwide occupational exposure to VC still seems to be high in some countries (e.g., averages of approximately 1,300 mg/m(3) until 1987 in one factory), and exposure may also be high in others where VC is not regulated. By combining the most relevant epidemiologic studies from several countries, we observed a 5-fold excess of liver cancer, primarily because of a 45-fold excess risk from angiosarcoma of the liver (ASL). The number of ASL cases reported up to the end of 1998 was 197 worldwide. The average latency for ASL is 22 years. Some studies show a small excess risk for hepatocellular carcinoma, and others suggest a possible risk of brain tumors among highly exposed workers. Lung cancer, lymphomas, or leukemia do not seem to be related to VC exposure according to recent results. The mutation spectra observed in rat and human liver tumors (ASL and/or hepatocellular carcinoma) that are associated with exposure to VC are clearly distinct from those observed in sporadic liver tumors or hepatic tumors that are associated with other exposures. In rats, the substitution mutations found at A:T base pairs in the ras and p53 genes are consistent with the promutagenic properties of the DNA adduct 1,N(6)-ethenoadenine formed from VC metabolites. Risk assessments derived from animal studies seem to overestimate the actual risk of cancer when comparing estimated and reported cases of ASL.ImagesFigure 1Figure 2

Environmental hazard assessments for chemicals are carried out to define an environmentally "safe" level at which, theoretically, the chemical will not negatively affect any exposed biota. Despite this common goal, the methodologies in use are very diverse across different countries and jurisdictions. This becomes particularly obvious when international scientists work together on documents with global scope, e.g., in the World Health Organization (WHO) International Program on Chemical Safety. In this article, we present a study that describes the extent of such variability and analyze the reasons that lead to different outcomes in deriving a "safe level" (termed the predicted no effect concentration [PNEC] throughout this article). For this purpose, we chose 5 chemicals to represent well-known substances for which sufficient high-quality aquatic effects data were available: ethylene glycol, trichloroethylene, nonylphenol, hexachlorobenzene, and copper (Cu). From these data, 2 data sets for each chemical were compiled: the full data set, that contained all information from selected peer-review sources, and the base data set, a subsample of the full set simulating limited data. Scientists from the European Union (EU), United States, Canada, Japan, and Australia independently carried out hazard assessments for each of these chemicals using the same data sets. Their reasoning for key study selection, use of assessment factors, or use of probabilistic methods was comprehensively documented. The observed variation in the PNECs for all chemicals was up to 3 orders of magnitude, and this was not simply due to obvious factors such as the size of the data set or the methodology used. Rather, this was due to individual decisions of the assessors within the scope of the methodology used, especially key study selection, acute versus chronic definitions, and size of assessment factors. Awareness of these factors, together with transparency of the decision-making process, would be necessary to minimize confusion and uncertainty related to different hazard assessment outcomes, particularly in international documents. The development of a "guideline on transparency in decision-making" ensuring the decision-making process is science-based, understandable, and transparent, may therefore be a promising way forward.

As part of a larger literature study on transgenic animals in mutagenicity testing, test results from the transgenic mutagenicity assays (lacI model; commercially available as the Big Blue® mouse, and the lacZ model; commercially available as the Muta™Mouse), were compared with the results on the same substances in the more traditional mouse bone marrow micronucleus test. 39 substances were found which had been tested in the micronucleus assay and in the above transgenic mouse systems. Although, the transgenic animal mutation assay is not directly comparable with the micronucleus test, because different genetic endpoints are examined: chromosome aberration versus gene mutation, the results for the majority of substances were in agreement. Both test systems, the transgenic mouse assay and the mouse bone marrow micronucleus test, have advantages and they complement each other. However, the transgenic animal assay has some distinct advantages over the micronucleus test: it is not restricted to one target organ and detects systemic as well as local mutagenic effects.