Application of physiologically-based pharmacokinetic modeled toluene blood concentration in the assessment of short term exposure limits.

Toluene is a volatile hydrocarbon with solvent applications in several industries. Acute neurological effects in workers exposed to toluene have been reported in various publications. To inform the basis for a toluene Short Term Exposure Limit (STEL), studies of toluene-exposed workers were modeled using customized exposure scenarios within an existing physiologically-based pharmacokinetic (PBPK) model to simulate blood concentrations during individual studies. Maximum simulated blood concentration ranged from 0.3 to 1.7 (mean = 0.74 mg/L, median = 0.73, upper 95th percentile = 1.07) at the studies identified No Observed Adverse Effect Concentration (NOAEC). Maximum simulated blood concentration ranged from 0.7 to 4.1 mg/L (mean = 1.81, median = 1.63, lower 95th percentile = 0.92) at the studies identified Lowest Observed Adverse Effect Concentration (LOAEC). The maximum blood concentration for a 100 ppm STEL-like simulation was 0.4 mg/L, at the lower end of the NOAEC range and below the 95th percentile of the LOAEC. Therefore, it appears that a STEL <100 ppm would be unnecessary to protect workers due to peak occupational exposures to toluene.

Appraisal of the human health related toxicological information available on dicyclopentadiene (DCPD) in view of assessing the substance's potential to cause endocrine disruption.

Dicyclopentadiene (DCPD) is an olefinic hydrocarbon which is manufactured and imported into the European Union (EU) at greater than 1000 tons per year. Concerns related to fetotoxic effects observed in reproductive toxicity studies at high doses led the REACH registrants to self-classify DCPD as a Category 2 reproductive toxicant under the EU CLP Regulation. DCPD was also reviewed in the European Union in the frame of an ongoing European Chemical Agency (ECHA) Community Rolling Action Plan (CoRAP) procedure and under the French National Strategy on Endocrine Disruptors (SNPE). To elucidate whether the developmental effects may be triggered by an endocrine mode of action, the Lower Olefins Sector Group (LOSG) of the European Chemical Industry Council (CEFIC) formed an ad hoc expert team to review the available scientific information pertaining to the potential endocrine activity and adversity of DCPD. Existing experimental data was complemented with structure activity modelling using ECHA-recommended (Q)SAR tools. Overall, considering the available information from (Q)SAR, mechanistic in vitro and in vivo studies, no indication of endocrine-mediated adversity was found. Hence, the available evidence supports the conclusion that DCPD does not cause developmental toxicity via an endocrine mode of action. Further work is ongoing to support this conclusion.

Chronic exposure to low concentrations of strontium 90 affects bone physiology but not the hematopoietic system in mice.

The aim of this work was to delineate the effects of chronic ingestion of strontium 90 ((90) Sr) at low concentrations on the hematopoiesis and the bone physiology. A mouse model was used for that purpose. Parent animals ingested water containing 20 kBq l(-1) of (90) Sr two weeks before mating. Offspring were then continuously contaminated with (90) Sr through placental transfer during fetal life, through lactation after birth and through drinking water after weaning. At various ages between birth and 20 weeks, animals were tested for hematopoietic parameters such as blood cell counts, colony forming cells in spleen and bone marrow and cytokine concentrations in the plasma. However, we did not find any modification in (90) Sr ingesting animals as compared with control animals. By contrast, the analysis of bone physiology showed a modification of gene expression towards bone resorption. This was confirmed by an increase in C-telopeptide of collagen in the plasma of (90) Sr ingesting animals as compared with control animals. This modification in bone metabolism was not linked to a modification of the phosphocalcic homeostasis, as measured by calcium, phosphorus, vitamin D and parathyroid hormone in the blood. Overall these results suggest that the chronic ingestion of (90) Sr at low concentration in the long term may induce modifications in bone metabolism but not in hematopoiesis.

Biokinetics of 90Sr after chronic ingestion in a juvenile and adult mouse model.

The aim of our study was to define the biokinetics of (90)Sr after chronic contamination by ingestion using a juvenile and adult murine model. Animals ingested (90)Sr by drinking water containing 20 kBq l(-1) of (90)Sr. For the juvenile model, parents received (90)Sr before mating and their offspring were killed between birth and 20 weeks of ingestion. For the adult model, (90)Sr ingestion started at 9 weeks of age and they were killed after different ingestion periods up to 20 weeks. The body weight, food and water consumption of the animals were monitored on a weekly basis. Before killing and sampling of organs, animals were put in metabolic cages. (90)Sr in organs and excreta was determined by liquid scintillation ß counting. Highest (90)Sr contents were found in bones and were generally higher in females than in males, and (90)Sr retention varied according to the skeletal sites. An accumulation of (90)Sr in the bones was observed over time for both models, with a plateau level at adult age for the juvenile model. The highest rate of (90)Sr accumulation in bones was observed in early life of offspring, i.e. before the age of 6 weeks. With the exception of the digestive tract, (90)Sr was below the detection limit in all other organs sampled. Overall, our results confirm that (90)Sr mainly accumulates in bones. Furthermore, our results indicate that there are gender- and age-dependent differences in the distribution of (90)Sr after low-dose chronic ingestion in the mouse model. These results provide the basis for future studies on possible non-cancerous effects during chronic, long-term exposure to (90)Sr through ingestion in a mouse model, especially on the immune and hematopoietic systems.

Immune System Modifications Induced in a Mouse Model of Chronic Exposure to (90)Sr.

Strontium 90 ((90)Sr) remains in the environment long after a major nuclear disaster occurs. As a result, populations living on contaminated land are potentially exposed to daily ingesting of low quantities of (90)Sr. The potential long-term health effects of such chronic contamination are unknown. In this study, we used a mouse model to evaluate the effects of (90)Sr ingestion on the immune system, the animals were chronically exposed to (90)Sr in drinking water at a concentration of 20 kBq/l, for a daily ingestion of 80-100 Bq/day. This resulted in a reduced number of CD19(+) B lymphocytes in the bone marrow and spleen in steady-state conditions. In contrast, the results from a vaccine experiment performed as a functional test of the immune system showed that in response to T-dependent antigens, there was a reduction in IgG specific to tetanus toxin (TT), a balanced Th1/Th2 response inducer antigen, but not to keyhole limpet hemocyanin (KLH), a strong Th2 response inducer antigen. This was accompanied by a reduction in Th1 cells in the spleen, consistent with the observed reduction in specific IgG concentration. The precise mechanisms by which (90)Sr acts on the immune system remain to be elucidated. However, our results suggest that (90)Sr ingestion may be responsible for some of the reported effects of internal contamination on the immune system in civilian populations exposed to the Chernobyl fallout.

Is toluene diamine a sensitizer and is there cross-reactivity between toluene diamine and toluene diisocyanate?

Toluene diamine (TDA) is formed when toluene diisocyanate (TDI), a potent sensitizer, comes in contact with an aqueous environment. The sensitizing capacity of TDA and the cross-reactivity between TDI and TDA are unknown. TDA (5-25%) and TDI (0.3%), dissolved in acetone/olive oil (AOO) (4:1) were tested in the mouse local lymph node assay (LLNA). To determine the capacity of TDA to elicit an asthmatic response and to determine the cross-reaction with TDI, a locally developed experimental mouse model of chemical-induced asthma was used. On days 1 and 8, BALB/c mice received 20 microl of TDI (0.3%), TDA (20%), or AOO (4:1) on each ear. On day 15, they received an intranasal instillation of TDI (0.1%), TDA (0.5%) or AOO (3:2). The EC(3) of TDA in the LLNA is 19%. In the model of chemical-induced asthma, TDI induced a ventilatory response [increased Penh after challenge; increased airway hyperreactivity (AHR)], inflammatory changes (bronchoalveolar lavage neutrophils), and immunological changes (increased CD19(+) lymphocytes, IL-4 and total serum IgE), whereas TDA did not show any of these responses. Mice sensitized with TDI and challenged with TDA also did not show any airway or inflammatory response, although they had increased levels of total serum IgE. Mice sensitized with TDA and challenged with TDI did not show any response. According to the classification of sensitizers in the LLNA, TDA is a weak dermal sensitizer. In the experimental mouse model of chemical-induced asthma, TDA does not act as a respiratory sensitizer, at the concentration used. No cross-reactivity between TDI and TDA was found.