Background, Aim and Scope. In 2005 a comprehensive comparison of LCIA toxicity characterisation models was initiated by the UNEP-SETAC Life Cycle Initiative, directly involving the model developers of CalTOX, IMPACT 2002, USES-LCA, BETR, EDIP, WATSON, and EcoSense. In this paper we describe this model-comparison process and its results-in particular the scientific consensus model developed by the model developers. The main objectives of this effort were (i) to identify specific sources of differences between the models' results and structure, (ii) to detect the indispensable model components, and (iii) to build a scientific consensus model from them, representing recommended practice. Methods. A chemical test set of 45 organics covering a wide range of property combinations was selected for this purpose. All models used this set. In three workshops, the model comparison participants identified key fate, exposure and effect issues via comparison of the final characterisation factors and selected intermediate outputs for fate, human exposure and toxic effects for the test set applied to all models. Results. Through this process, we were able to reduce inter-model variation from an initial range of up to 13 orders of magnitude down to no more than 2 orders of magnitude for any substance. This led to the development of USEtox, a scientific consensus model that contains only the most influential model elements. These were, for example, process formulations accounting for intermittent rain, defining a closed or open system environment, or nesting an urban box in a continental box. Discussion. The precision of the new characterisation factors (CFs) is within a factor of 100-1000 for human health and 10-100 for freshwater ecotoxicity of all other models compared to 12 orders of magnitude variation between the CFs of each model respectively. The achieved reduction of inter-model variability by up to 11 orders of magnitude is a significant improvement.Conclusions. USEtox provides a parsimonious and transparent tool for human health and ecosystem CF estimates. Based on a referenced database, it has now been used to calculate CFs for several thousand substances and forms the basis of the recommendations from UNEP-SETAC's Life Cycle Initiative regarding characterization of toxic impacts in Life Cycle Assessment. Recommendations and Perspectives. We provide both recommended and interim (not recommended and to be used with caution) characterisation factors for human health and freshwater ecotoxicity impacts. After a process of consensus building among stakeholders on a broad scale as well as several improvements regarding a wider and easier applicability of the model, USEtox will become available to practitioners for the calculation of further CFs. Keywords: Consensus model, life cycle impact assessment, LCIA, characterization modelling, comparison, harmonisation, human exposure, toxic impact, human toxicity, freshwater ecotoxicity, comparative impact assessment, characterization factors 1 Background, Aim and Scope In ...

Epidemiological evidence indicates that avoidance of smoking, increased consumption of fruits and vegetables, and control of infections will have a major effect on reducing rates of cancer. Other factors include avoidance of intense sun exposure, increases in physical activity, and reduction of alcohol consumption and possibly red meat. A substantial reduction in breast cancer is likely to require modification of sex hormone levels, and development of practical methods for doing so is a high research priority. Resolution of the potential protective roles of specific antioxidants and other constituents of fruits and vegetables deserves major attention. Mechanistic studies of carcinogenesis indicate an important role of endogenous oxidative damage to DNA that is balanced by elaborate defense and repair processes. Also key is the rate of cell division, which is influenced by hormones, growth, cytotoxicity, and inflammation, as this determines the probability of converting DNA lesions to mutations. These mechanisms may underlie many epidemiologic observations.

Purpose The aim of this paper is to provide science-based consensus and guidance for health effects modelling in comparative assessments based on human exposure and toxicity. This aim is achieved by (a) describing the USEtox™ exposure and toxicity models representing consensus and recommended modelling practice, (b) identifying key mechanisms influencing human exposure and toxicity effects of chemical emissions, (c) extending substance coverage. Methods The methods section of this paper contains a detailed documentation of both the human exposure and toxic effects models of USEtox™, to determine impacts on human health per kilogram substance emitted in different compartments. These are considered as scientific consensus and therefore recommended practice for comparative toxic impact assessment. The framework of the exposure model is described in details including the modelling of each exposure pathway considered (i.e. inhalation through air, ingestion through (a) drinking water, (b) agricultural produce, (c) meat and milk, and (d) fish). The calculation of human health effect factors for cancer and non-cancer effects via ingestion and inhalation exposure respectively is described. This section also includes discussions regarding parameterisation and estimation of input data needed, including route-to-route and acute-to-chronic extrapolations. Results and discussion For most chemicals in USEtox™, inhalation, above-ground agricultural produce, and fish are the important exposure pathways with key driving factors being Electronic supplementary material The online version of this article (

The administration of chemicals at the maximum tolerated dose (MTD) in standard animal cancer tests is postulated to increase cell division (mitogenesis), which in turn increases rates of mutagenesis and thus carcinogenesis. The animal data are consistent with this mechanism, because a high proportion-about half-of all chemicals tested (whether natural or synthetic) are indeed rodent carcinogens. We conclude that at the low doses of most human exposures, where cell killing does not occur, the hazards to humans of rodent carcinogens may be much lower than is commonly assumed. carcinogenic effects at low levels. This idea evolved because it was expected that (i) only a small proportion of chemicals would have carcinogenic potential, (ii) testing at a high dose would not produce a carcinogenic effect unique to the high dose, and (iii) chemical carcinogenesis would be explained by the mutagenic potential of chemicals. However, it seems time to take account of new information suggesting that all three assumptions are wrong. Carcinogens Are Common in Rodent TestsIn current strategies to prevent human cancer, chronic rodent bioassays are the major source of information used to predict the risk to humans from chemical exposures. This paper addresses the issue of the role of cell division (mitogenesis) in animal cancer tests and the implications of an improved theory of mechanisms of carcinogenesis for the assessment of cancer hazards to the general population. In animal tests done at the maximum tolerated dose (MTD), about half of the chemicals tested are rodent carcinogens (1-7). We argue that the explanation for a high percentage of chemicals being carcinogens at the MTD is that these high doses stimulate mitogenesis, which increases rates of mutagenesis and carcinogenesis. While (8).The high proportion of carcinogens among chemicals tested at the MTD emphasizes the importance of understanding cancer mechanisms in order to determine the relevance of rodent cancer test results for humans.

This review discusses reasons why animal cancer tests cannot be used to predict absolute human risks. Such tests, however, may be used to indicate that some chemicals might be of greater concern than others. Possible hazards to humans from a variety of rodent carcinogens are ranked by an index that relates the potency of each carcinogen in rodents to the exposure in humans. This ranking suggests that carcinogenic hazards from current levels of pesticide residues or water pollution are likely to be of minimal concern relative to the background levels of natural substances, though one cannot say whether these natural exposures are likely to be of major or minor importance.