INRS activities on risk assessment of glycol ethers.

The occupational exposure assessment uses data from published sources, from Industry (most often from the producers), and from dedicated occupational exposure data bases, as well as evaluations using the EASE model (Estimation and Assessment of Substance Exposure). Atmospheric concentrations and characteristics of skin contacts are evaluated in different scenarios (such as manufacturing, formulating, main and most polluting uses) and sub-scenarios (e.g. warm water dilution). Air concentrations of EGBE are low during production (most often <0.5 mg/m(3)), incidental excursions being <50 mg/m(3); the "worst-case" mean concentration is proposed as 9 mg/m(3). Skin contact, according to EASE, may be in the range of 0-0.1 mg/cm(2)(day), and should be mitigated by the use of suitable gloves. For formulations of products containing EGBE, air concentrations are evaluated as 10 mg/m(3) and skin contact as 0.19 mg/cm(2)(day). The "reasonable worst case" air concentrations (8-Hr TWA) are assessed at around 11 mg/m(3) (coating industry), from 5 to 20 mg/m(3) in printing activities (depending on the task), and in the 20-70 mg/m(3) range (upper limit 40 mg/m(3) in better controlled situations) for cleaning activities. Skin contact would be around twice the preceding level, i.e., 0.4 mg/cm(2)(day) for coating as well as cleaning activities. EGBE and its major metabolites, 2-butoxyacetaldehyde (2-BAL) and 2-butoxyacetic acid (2-BAA) have been subjected to tests for genetic toxicity tests both in vitro and in vivo. While some positive responses have been obtained, the balance of the evidence indicates that EGBE does not express significant genotoxic activity. There are no epidemiological data investigating a relationship between exposure to EGBE and human cancer. Two carcinogenicity inhalation bioassays have been conducted in rodents, one in rats and one in mice. Significant increases were found in forestomach tumours in female mice and haemangiosarcomas in male mice. No increases in tumour incidences were found in either male or female rats. Mechanistic studies have suggested the crucial involvement in the pathogenesis of haemangiosarcomas of a chain of events consisting of (1) haemolysis due to BAA, followed by (2) hepatic haemosiderin deposition and (3) the subsequent generation of reactive oxygen species within the endothelial cells from which haemangiosarcomas arise. Since human erythrocytes are particularly resistant to the haemolytic effects of BAA, it is extremely unlikely, according to this model, that the haemangiosarcomas observed in male mice will have human significance. Similarly, mechanistic studies on the female mouse forestomach tumours have suggested that these also are not important as an indication of human risk. In vivo, EGBE tested in a continuous breeding study and in repeated dose toxicity tests, did not produced specific effects on reproductive organs or fertility parameters. For developmental toxicity, rats, mice and rabbits were dosed via oral and/or inhalation routes. Foeto- and embryo-toxicity was observed in presence or maternal toxicity (haemolytic anaemia). The data available give plausible support to the hypothesis that this developmental toxicity is a direct consequence of maternal toxicity. There are no epidemiological data investigating a relationship between exposure to EGBE alone and human reproductive effects.

The PERICLES research program: an integrated approach to characterize the combined effects of mixtures of pesticide residues to which the French population is exposed.

Due to the broad spectrum of pesticide usages, consumers are exposed to mixtures of residues, which may have combined effects on human health. The PERICLES research program aims to test the potential combined effects of pesticide mixtures, which are likely to occur through dietary exposure. The co-exposure of the French general population to 79 pesticide residues present in the diet was first assessed. A Bayesian nonparametric model was then applied to define the main mixtures to which the French general population is simultaneously and most heavily exposed. Seven mixtures made of two to six pesticides were identified from the exposure assessment. An in vitro approach was used for investigating the toxicological effects of these mixtures and their corresponding individual compounds, using a panel of cellular models, i.e. primary rat and human hepatocytes, liver, intestine, kidney, colon and brain human cell lines. A set of cell functions and corresponding end-points were monitored such as cytotoxicity, real-time cell impedance, genotoxicity, oxidative stress, apoptosis and PXR nuclear receptor transactivation. The mixtures were tested in equimolar concentrations. Among the seven mixtures, two appeared highly cytotoxic, five activated PXR and depending on the assay one or two were genotoxic. In some experiments, the mixture effect was quantitatively different from the effect expected from the addition concept. The PERICLES program shows that, for the most pesticides mixtures to which the French general population is exposed, the toxic effects observed on human cells cannot be easily predicted based on the toxic potential of each compound. Consequently, additional studies should be carried on in order to more accurately define the mixtures of chemicals to which the consumers are exposed, as well as to improve the investigation, prediction and monitoring of their potential human health effects.