Some aromatic solvents (e.g. toluene, p-xylene, styrene, and ethylbenzene) show, in the rat, striking ototoxicity characterized by an irreversible hearing loss, as measured by behavioural or electrophysiological methods, associated with damage to outer hair cells in the cochlea of the exposed animals. To broaden the range of aromatic solvents studied concerning their potential ototoxicity and to compare their ototoxicity quantitatively, 21 aromatic solvents were administered orally by gastric intubation to Sprague-Dawley rats for 5 days/week for a 2-week period. The dose used was 8.47 mmol kg(-1) body weight day(-1). The possible ototoxicity of the aromatic solvents was evaluated by morphological investigation of the cochlea. Whole-mount surface preparations of the organ of Corti were made to quantify the number of missing hair cells (cytocochleogram). Among the 21 solvents studied, eight (toluene, p-xylene, ethylbenzene, n-propylbenzene, styrene, alpha-methylstyrene, trans-beta-methylstyrene, and allylbenzene) caused histological lesions of the organ of Corti. They differed widely in their potency. The least ototoxic solvents caused outer hair cell (OHC) loss in the middle turn of the organ of Corti. The OHC loss was slight in the first row, and greater in the second and third rows. The most ototoxic solvents caused high losses in the three rows of the outer hair cells along the entire length of the basilar membrane. There were also occasional inner hair cell (ICH) losses in the most affected animals. Although no measurements were made of the chemical concentrations reached in the blood or the brain, tentative ranking of an increasing ototoxicity of the eight aromatic solvents could be proposed on the basis of the histological losses observed-alpha-methylstyrene
Notwithstanding potential neurotoxicity of inhaled titanium dioxide nanoparticles (TiO2 NPs), the toxicokinetics and consequences on blood-brain barrier (BBB) function remain poorly characterized. To improve risk assessment, we need to evaluate the impact on BBB under realistic environmental conditions and take into account vulnerability status such as age. 12–13 week and 19-month-old male rats were exposed by inhalation to 10 mg/m3 of TiO2 nano-aerosol (6 hrs/day, 5 day/week, for 4 weeks). We showed an age-dependent modulation of BBB integrity parameters suggesting increased BBB permeability in aging rats. This alteration was associated with a significant increase of cytokines/chemokines in the brain, including interleukin-1β, interferon-γ, and fractalkine as well as a decreased expression of synaptophysin, a neuronal activity marker. These observations, in absence of detectable titanium in the brain suggest that CNS-related effects are mediated by systemic-pathway. Moreover, observations in terms of BBB permeability and brain inflammation underline age susceptibility. Even if TiO2 NPs were not evidenced in the brain, we observed an association between the exposure to TiO2 NPs and the dysregulation of BBB physiology associated with neuroinflammation and decreased expression of neuronal activity marker, which was further exacerbated in the brain of aged animal’s.
The expiratory bradypnoea indicative of upper airway irritation in mice was evaluated during a 60-min oronasal exposure to increasing concentrations of chlorine and nitrogen trichloride. The airborne concentration resulting in a 50% decrease in the respiratory rate of mice (RD50) was calculated for each chemical. Chlorine and nitrogen trichloride showed dissimilar concentration-response curves. While the maximal response of nitrogen trichloride was reached in 10 min, the maximal response of chlorine was reached between 45 and 60 min of exposure. The results showed both chemicals to have an irritant potency of the same order of magnitude. The RD50 values of chlorine and nitrogen trichloride were 3.5 and 2.5 ppm, respectively. On the basis of a TLV-STEL (threshold limit value for short-term exposure limit) equal to 0.1 RD50 and a TLV-TWA (time-weighted average) equal to 0.03 RD50, the current TLVs for chlorine seem too high (1 and 0.5 ppm, respectively) and should be reduced to 0.5 and 0.1 ppm, respectively. For nitrogen trichloride, 0.3 ppm and 0.1 ppm are proposed as TLV-STEL and TLV-TWA, respectively.
The commercial isomer mixture of diethylbenzene (DEB mixture), 1,2-diethylbenzene (1,2-DEB), 1,3-diethylbenzene (1,3-DEB) and 1,4-diethylbenzene (1,4-DEB) were administered orally to male Sprague-Dawley rats. The experimental rats and the appropriate controls were examined electrophysiologically for motor and sensory conduction velocities (MCV and SCV), and for the amplitude of the sensory action potential (ASAP) of the tail nerve, at weekly or bi-weekly intervals. Oral administration of DEB mixture (750 or 500 mg kg-1, once daily, 5 days per week for 10 weeks) and 1,2-DEB (100 mg kg-1, once daily, 4 days per week for 8 weeks) produced a time-dependent decrease in MCV, SCV and ASAP. Rats treated with DEB mixture and 1,2-DEB exhibited a blue discoloration of tissues and urine. No changes in MCV, SCV and ASAP developed in rats administered orally with 1,3-DEP and 1,4-DEB (500 mg kg-1, once daily, 5 days per week for 8 weeks). The results indicate that 1,2-DEB is the isomer responsible for neurotoxicity and suggest that a metabolic pathway giving rise to coloured compounds is involved in the neurotoxicity of DEB.
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