Penetration of ammonium perfluorooctanoate through rat and human skin in vitro.

Rat and human epidermal membranes were mounted onto in vitro diffusion cells with an exposure area of 0.64 cm2, and skin integrity was confirmed using electrical impedance. Following membrane selection, Fluorad FC-118, a 20% aqueous solution of ammonium perfluorooctanoate (AFPO), was applied to the epidermal surface of each skin replicate at approximately 150 microL/cm2 and the donor chamber opening occluded with Parafilm. Serial receptor fluid samples were collected hourly from 1 to 6 h and at 12, 24, 30, and 48 h and analyzed by liquid chromatography-mass spectrometry (LC-MS) for APFO anion (PFO-). For rat skin, the time to steady-state penetration (6500+/-3000 ng APFO x cm(-2) x h(-1)) occurred in less than 12 h, which was sustained until termination (48 h). Based on the concentration of the applied test material, the permeability coefficient (Kp) for APFO in rat skin was calculated to be 3.25+/-1.51 x 10(-5) cm/h. By end of the 48-h exposure period, only a small portion of the total APFO applied (1.44+/-1.13%) had penetrated through rat skin. For human skin, steady-state penetration of APFO (190+/-57 ng APFO x cm(-2) x h(-1)) was reached by 12 h. Based on the concentration of the applied test material, the permeability coefficient for APFO in human skin was calculated to be 9.49+/-2.86 x 10(-7) cm/h. By the end of the 48-h exposure period, only a negligible amount of the total APFO applied (0.048+/-0.01%) had penetrated through human skin. Thus, under infinite dose and occlusive conditions, the steady-state penetration of APFO from a 20% solution was approximately 34-fold faster through rat skin than human skin.

Mortality of workers exposed to methylene chloride employed at a plant producing cellulose triacetate film base.

OBJECTIVE: To study mortality among 1785 employees of a factory that produced cellulose triacetate film base at Brantham in the United Kingdom. Also, to investigate patterns of mortality after exposure to methylene chloride; in particular, mortality from liver and biliary tract cancer, lung cancer, pancreatic cancer, and cardiovascular disease. SUBJECTS AND METHODS: All male employees with a record of employment at the film factory in 1946-88. A total of 1473 subjects worked in jobs that entailed exposure to methylene chloride. The mean duration of exposure was nine years at 19 ppm (eight hour time weighted average). RESULTS: In the cohort, 334 deaths were identified up to 31 December 1994. Mortalities for the cohort were compared with national and local rates and expressed as standardised mortality ratios (SMR). In the subcohort of workers exposed to methylene chloride, substantially reduced mortalities compared with national and local rates were found for all causes, all cancers, and the principal cancer sites of interest. The significantly reduced lung cancer mortalities in exposed workers (SMR 48) seemed to reflect the restrictions on smoking at the workplace. In contrast, mortality from ischaemic heart disease in exposed workers, although lower than national rates (SMR 92), was slightly increased compared with local rates. However, mortality from ischaemic heart disease was lower in active employees (SMR 83) where a direct effect of exposure to methylene chloride should be concentrated. No in service mortality due to ischaemic heart disease was found in workers with the highest cumulative exposure (> or = 800 ppm-years). CONCLUSIONS: The study provided no indication that employment at the plant, or exposure to methylene chloride, had adversely affected the mortalities of workers.

Health risk assessment of environmental exposure to trichloroethylene.

A review of the animal data showed trichloroethylene (TRI) to be of low acute toxicity. Repeated exposure showed that the target organs were the liver, and to a lesser extent, the kidney. TRI is not mutagenic or only marginally mutagenic. There is no evidence of fetotoxicity or teratogenicity. TRI is judged not to exhibit chronic neurotoxicity. Lifetime bioassays resulted in tumors in both the mouse and the rat. However, because of qualitative and quantitative metabolic differences between rodent and human, no one suitable tumor site can be chosen for human health risk assessment. In addition, of the several epidemiology studies, none has demonstrated a positive association for increased tumor incidence. A review of the health effects in humans shows TRI to be of low acute toxicity and, following chronic high doses, to be hepatotoxic. Environmental exposure to TRI is mainly via the atmosphere, while the contribution from exposure to drinking water and foodstuffs is negligible. The total body burden was calculated as 22 micrograms/day. The safety margin approach based on human health effects showed that TRI levels are well within the safety margin for the human no-observable-effect level (10,000 times lower). The total body burden represents a risk of 1.4 X 10(-5) by linearized multistage modeling. Therefore, by either methodological approach to risk assessment, the environmental occurrence of TRI does not represent a significant health risk to the general population or to the population in areas close to industrial activities.

Pharmacological studies with adenine, adenosine and some phosphorylated derivatives on guinea-pig tracheal muscle.

Adenine, adenosine and three adenine nucleotides all caused relaxation of the guinea-pig trachea. The relaxation to the nucleotides was often preceded by a contraction. The response to adenosine and the nucleotides, but not adenine, was potentiated by dipyridamole. Imidazole inhibited the response to adenine alone. Propranolol has no effect on the response to any of the compounds. It is concluded that the guinea-pig trachea does not possess and a nucleotide-specific receptor as has been postulated for some other smooth muscle preparations. An alternative hypothesis postulating an adenosine-specific receptor is presented.

Antagonism of tone and prostaglandin-mediated responses in a tracheal preparation by indomethacin and SC-19220.

1 The effects of the prostaglandin synthetase inhibitor, indomethacin and the prostaglandin antagonist SC-19220 (1-acetyl-2-[8-chloro-10,11-dihydrodibenz (b,f) (1,4)oxazepine-10-carbonyl] hydrazine), were examined on the tone of the guinea-pig isolated tracheal preparation and on the responses of the preparation to prostaglandin F(2alpha), arachidonic acid and methacholine.2 Indomethacin (0.05-1.6 mug/ml) produced a long-lasting inhibition of the intrinsic tone of the tracheal preparation and of the contractile responses to arachidonic acid. Much higher concentrations of indomethacin also reduced the responses of the preparation to methacholine. This effect was readily reversible and appeared to be unrelated to the action on tone.3 The contractile responses of the preparation to prostaglandin F(2alpha) were enhanced by low concentrations of indomethacin (1-5 mug/ml) and inhibited by higher concentrations (2.5-80 mug/ml).4 SC-19220 was shown to inhibit responses of the preparation to prostaglandin F(2alpha) in concentrations (0.1-1 mug/ml) which had no effect on responses to methacholine. Similar concentrations also inhibited the intrinsic tone of the preparation and the responses to arachidonic acid.5 The evidence suggests that prostaglandins may be involved in the maintenance of tone of the guinea-pig isolated tracheal preparation.