RESUMEN
There is potential for human exposure to cyclic siloxanes by the respiratory route. To determine the pharmacokinetics of octamethylcyclotetrasiloxane (D4), a material commonly found in personal care products, the respiratory intake and uptake of D4 were measured in 12 healthy volunteers (25-49 years) on two occasions. Subjects inhaled 10 ppm D4 (122 micrograms/liter) or air (control) during a 1-h exposure via a mouthpiece in a double-blind, randomized fashion. Inspiratory and expiratory D4 concentrations were continuously measured. Exhaled air and plasma D4 levels were measured before, during, and after exposures. Individual D4 uptakes were measured under steady-state conditions during three rest periods (10, 20, and 10 min, respectively) alternating with two 10-min exercise periods. Mean D4 intake was 137 +/- 25 mg (SD) and the mean deposition efficiency was equivalent to 0.74/(1 + 0.45 VE), where VE is the minute ventilation. No changes in lung function were induced by the D4 vapor. Plasma measurements of D4 gave a mean peak value of 79 +/- 5 ng/g (SEM) and indicated a rapid nonlinear blood clearance. Using lung volume and respiratory surface area estimates based on functional residual capacity measurements, we developed a model and determined that the effective mass transfer coefficient for D4 was 5.7 x 10(-5) cm/s from lung air to blood. In an additional eight subjects, we compared D4 deposition with mouthpiece and nasal breathing at resting ventilations. For these individuals, mean deposition was similar for the two exposure protocols, averaging 12% after correction for exposure system losses. These are the first data describing the intake and absorption of D4 and they should contribute to a meaningful safety assessment of the compound.
Asunto(s)
Siloxanos/farmacocinética , Adulto , Método Doble Ciego , Femenino , Humanos , Pulmón/efectos de los fármacos , Pulmón/fisiología , Masculino , Persona de Mediana Edad , Siloxanos/administración & dosificación , Siloxanos/toxicidad , VolatilizaciónRESUMEN
Humans are exposed to silicones in a number of commercial and consumer products. Some of these silicones, including octamethylcyclotetrasiloxane (D4), are volatile. Therefore, there is a potential for respiratory exposure. A pharmacokinetic analysis of respiratory exposure to D4 is presented in the accompanying paper (M. J. Utell et al., 1998, Toxicol. Sci. 44, 206-213). Possible immune effects of respiratory exposure to D4 are investigated in this paper. Normal volunteers were exposed to 10 ppm D4 or air for 1 h via a mouthpiece using a double-blind, crossover study design. Assays were chosen to screen for immunotoxicity or a systemic inflammatory response. Assessment of immunotoxicity included enumeration of peripheral lymphocyte subsets and functional assays using peripheral blood mononuclear cells. Because in humans there is no direct test for adjuvant effect of respiratory exposure, we analyzed proinflammatory cytokines and acute-phase reactants in peripheral blood, markers for a systemic inflammatory response, as surrogate markers for adjuvancy. These tests were repeated when the volunteers were reexposed to D4 approximately 3 months after this initial exposure. Blood was obtained prior to exposure, immediately postexposure, and 6 and 24 h postexposure. In these short-term, controlled human exposures, no immunotoxic or proinflammatory effects of respiratory exposure to D4 were found.
Asunto(s)
Inmunidad/efectos de los fármacos , Pulmón/efectos de los fármacos , Siloxanos/toxicidad , Adulto , Citocinas/biosíntesis , Citocinas/sangre , Femenino , Humanos , Pulmón/fisiología , Activación de Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Siloxanos/administración & dosificación , Siloxanos/farmacocinéticaRESUMEN
Inhaled CdCl2 is a pulmonary carcinogen in rats but not in mice. We hypothesized that pulmonary metallothionein (MT) induction may be different in both species and thereby may lead to different levels of protection from Cd-induced lung injury. Fisher-344 rats and B6C3F1 mice were exposed for 4 weeks to CdCl2 aerosols of 0, 30, 50, and 150 micrograms/m3 air or 0, 10, 30, and 100 micrograms/m3 air, respectively. Animals from each exposure group were terminated at 1, 30 and 133 days after the end of exposure. The lungs were lavaged for cell and biochemical analyses. Cadmium and MT in lavagate and lung tissue were measured. The retention half-time of pulmonary Cd was greater in mice (290 vs 90 days, p < 0.05). Cd exposure provoked an inflammatory response which was dose-dependent in both species, and while it was only short-lived in rats, it persisted throughout the observation period in mice at the high exposure concentrations. Mice were found to have a greater baseline level of MT (18.04 +/- 6.96 vs 11.7 +/- 1.98 micrograms MT/g control lung, p < 0.05). Mice showed greater inducibility of MT for a given CdCl2 exposure concentration; however, both species had a similar relationship between retained pulmonary Cd and MT induction though mice maintained increased MT levels for a longer period of time. The greater pulmonary baseline MT together with the longer presence of Cd-induced pulmonary MT may result in greater protection from Cd carcinogenicity in spite of the greater pulmonary Cd-induced inflammation in mice.