J. de Ceaurriz

Sensory irritation caused by various industrial airborne chemicals

A short inhalation experiment was performed on mice using 22 industrial airborne irritants. The parameter chosen as an index of sensory irritation was the reflex decrease in respiratory rate. For each compound, systematic determination of the concentration associated with a 50% decrease in the respiratory rate (RD50) permitted, on the basis of the same end point, a comparison of their relative potencies. The possibility of using the obtained data as initial guidelines to establish acceptable Threshold Limit Values (TLVs) in the workplace was examined.

Role of γ-glutamyltranspeptidase and β-lyase in the nephrotoxicity of hexachloro-1,3-butadiene and methyl mercury in mice

Abstract Male Swiss OF1 mice received a single oral dose of either 80 mg kg hexachloro-1,3-butadiene (HCBD) or 80 mg kg methyl mercury (MeHg). Examination of cryostat kidney sections stained for alkaline phosphatase (APP) revealed damage to about 50% of the proximal tubules after 8 h. Pretreatment with the γ-glutamyltranspeptidase (γ-GT) inactivator AT-125 (Acivin, 50 mg kg i.p., plus 50 mg kg p.o., reduced the number of damaged tubules by 59 and 58% in mice treated with HCBD and MeHg, respectively. Pretreatment with the two β-lyase inhibitors, amino-oxyacetic acid (AOAA, 3 × 100 mg kg p.o.) and dl -propargylglycine (PPG, 300 mg kg i.p. plus 300 mg kg p.o), reduced HCBD nephrotoxicity by 46 and 59%, respectively, but did not protect against MeHg nephrotoxicity. The results support a role for γ-GT and β-lyase in the mouse renal toxicity of HCBD and implicate γ-GT but not β-lyase in MeHg-induced nephrotoxicity in mice.

The effects of maternally inhaled formaldehyde on embryonal and foetal development in rats

Sprague-Dawley rats were exposed to 0, 5, 10, 20 or 40 ppm formaldehyde for 6 hr/day from day 6 to 20 of gestation. On day 21 of gestation the rats were killed for evaluation of maternal reproductive and foetal parameters. No effect on embryonic or foetal lethality, nor significant alterations in the external, visceral or skeletal appearance of the foetuses were noted in any of the exposed groups. Significant concentration-related reduction of foetal body weight occurred at 20 and 40 ppm, and at 40 ppm foetal body weights were 20% less than those of the controls. Maternal toxicity, indicated by significant reduction in body weight and absolute weight gain, was observed at 40 ppm. The results of this study show that formaldehyde is slightly foetotoxic at 20 ppm. Neither embryolethal nor teratogenic effects were observed following inhalation exposure at levels up to 40 ppm.

Effects of inhalation exposure to carbon disulfide and its combination with hydrogen sulfide on embryonal and fetal development in rats

Pregnant rats were exposed to 0, 100, 200, 400 or 800 ppm of carbon disulfide (CS2), 100 ppm of hydrogen sulfide (H2S) alone or in combination with 400 and 800 ppm CS2, 6 h/d during days 6-20 of gestation. Maternal reproduction and fetal parameters were evaluated on gestational day 21. Treatment with 100 or 200 ppm CS2 or with 100 ppm H2S caused no maternal toxicity or adverse effects on the developing embryo or fetus. Exposure to 400 or 800 ppm CS2 resulted in a low incidence of club foot and in a significant reduction of maternal weight gain. Significant increases in unossified sternebrae occurred at 800 ppm CS2 and reduction of fetal body weight at 400 and 800 ppm CS2. The latter effect was enhanced by combination with 100 ppm H2S. These results support the conclusion that, at levels of exposure associated with maternal toxicity, CS2 leads to an increase in incidence of club foot and to fetal toxicity which is enhanced by simultaneous exposure to H2S.

Short-term inhalation test for evaluating industrial hepatotoxicants in rats

Liver damage was investigated in rat using serum enzyme activities measurements. Responses were recorded 24 h after whole body inhalation exposure to vapors of bromobenzene, carbon tetrachloride, chloroform, o-dichlorobenzene, 1,2-dichloroethane and dimethylformamide as model toxicants. First, rats were exposed during a single 4 h period to different concentrations of each solvent and the minimally active concentration was determined. Second, repeated exposures to chemicals at this concentration level (6 h daily, 2 or 4 days) were used in order to examine whether hepatotoxicity was enhanced. GLDH and SDH are more sensitive and more constant indices than GOT and GPT. It appears that a single exposure period induced more marked serum activities enhancement than repeated exposures.

Evaluation of the interaction of benzene and toluene on the urinary excretion of t, t-muconic acid in rats

The influence of simultaneous exposure to benzene and toluene on the urine excretion of t,t-muconic acid (t,t-MA) was examined in rats. t,t-MA was measured from 24-h urine of rats subjected to a single 4-h exposure to 5 or 20 ppm benzene and/or 50, 100, 200 or 1000 ppm toluene. Coexposure lowered t,t-MA excretion in a concentration-dependent manner, especially in the 20 ppm benzene group where the decrease averaged 28, 44 and 85% after exposure to 100, 200 and 1000 ppm toluene, respectively, as compared to benzene-exposed groups alone. The data confirm the sensitivity of t,t-MA as an indicator of benzene exposure and point out that measurement of t,t-MA may underestimate the exposure to benzene in the presence of toluene.

Relative Developmental Toxicities of Inhaled Aliphatic Mononitriles in Rats

The developmental toxicities of eight aliphatic mononitriles were studied in Sprague-Dawley rats after inhalation exposure for 6 hr/day, during Days 6 to 20 of gestation. The range of exposure concentrations for acetonitrile was 900 to 1800 ppm; for propionitrile and n-butyronitrile, 50 to 200 ppm; for isobutyronitrile, 50 to 300 ppm; for acrylonitrile and methacrylonitrile, 12 to 100 ppm; for allylnitrile 12 to 50 ppm; and for 2-chloroacrylonitrile, 1 to 12 ppm. Embryolethality was observed after exposure to 1800 ppm acetonitrile, 200 ppm propionitrile, 300 ppm isobutyronitrile; fetotoxicity was observed after exposure to 200 ppm propionitrile, n-butyronitrile, or isobutyronitrile, or to 25 ppm acrylonitrile in the presence of overt signs of maternal toxicity. In the absence of significant maternal toxicity, allylnitrile caused embryolethality, fetotoxicity, and clear teratogenicity at 50 ppm, and n-butyronitrile and methacrylonitrile caused fetotoxicity at 200 ppm and 100 ppm, respectively. While maternal toxicity was observed for 2-chloroacrylonitrile, it did not cause significant embryonal or fetal toxicity up to 12 ppm.

Acetone compared to other ketones in modifying the hepatotoxicity of inhaled 1,2-dichlorobenzene in rats and mice.

The ability of acetone and 3 other ketone vapours to influence the hepatotoxicity of inhaled 1,2-dichlorobenzene (DCB) was examined in rats and mice. Methylethylketone, methylisobutylketone or cyclohexanone increased liver cytochrome P-450 content and glutathione-S-transferase (GST) activity, but did not affect serum glutamate dehydrogenase (GLDH) activity in rats. Pre-exposure to these ketones enhanced DCB-induced increase in serum GLDH activity (8-63-fold), while the increases in cytochrome P-450 content (33-86%) and GST activity (42-64%) were identical to those resulting from exposure to ketones alone. Each of the 3 levels of exposure to acetone elicited cytochrome P-450 and GST responses comparable with those caused by the other ketones. In spite of that, acetone pre-exposure potentiated (4785 ppm), reduced (10670 ppm) or suppressed (14790 ppm) DCB-induced liver toxicity. In mice, the 3 ketones mentioned above interacted with DCB on centrolobular liver glucose-6-phosphatase (G-6-Pase) while acetone pre-exposure elicited an interactive G-6-Pase response in the mediolobular area alone, suggesting topographic change.

Probenecid-induced protection against acute hexachloro-1, 3-butadiene and methyl mercury toxicity to the mouse kidney

Male Swiss OF1 mice received a single oral dose of either 80 mg/kg hexachloro-1,3-butadiene (HCBD) or 40 mg/kg methyl mercury (MeHg). Examination of cryostat kidney sections stained for alkaline phosphatase (APP) revealed damage to about 50% of the proximal tubules after 8 h. Treatment with the organic anion transport inhibitor probenecid (i.p., 3 x 0.75 mmol/kg) did not have any renal effect in normal mice but reduced the number of damaged tubules by 80 and 90% in mice treated with HCBD and MeHg respectively. The results support the conclusion that the toxicity of HCBD and MeHg to the mouse kidney is related to a probenecid-sensitive transport process. It cannot be stated from the present investigation whether the inhibition nephrotoxicity data are related to classic organic anion secretion by the kidney.

Experimental sensitization of guinea-pigs to nickel and patch testing with metal samples

Two groups each of 30 guinea-pigs were painted on 5 days/wk for 4 wk with 1% nickel sulphate in lanolin. The dose was applied to the shaved dorsal skin, which was prepared daily before treatment with sodium lauryl sulphate and injected intradermally each week during this period with 0.1 ml 1% potassium alum in distilled water, close to the site of NiSO4 application. Of the two groups of guinea-pigs submitted to this epicutaneous procedure, 63 and 80% developed skin allergy in response to challenge with 2% NiSO4 after a rest period of 2 wk, whereas no sensitization response was elicited by 1% NiSO4 in the guinea-pig maximization test. When two further groups were sensitized by the epicutaneous procedure, the first group, with a sensitization rate of 52% at the first challenge, showed no decline in response with five successive monthly challenges. Addition of NiCl2 to the drinking-water of the second group did not increase the sensitization rate induced by the monthly rechallenges with NiSO4. In guinea-pigs allergic to nickel, plating of Ni-coated brass discs with chromium as a special surface treatment prevented the occurrence of the contact allergy elicited by brass discs coated with Ni alone, whereas plating with gold/copper/cadmium did not.