1,1,1,2-Tetrafluoroethane: Repeat Exposure Inhalation Toxicity in the Rat, Developmental Toxicity in the Rabbit, and Genoxicity in Vitro and in Vivo

Subchronic and chronic studies were carried out in the rat anda developmental toxicity study in the rabbit with exposuresto 1,1,1,2-tetrafluoroethane (HFC 134a) by inhalation. In therat repeated exposure to 50,000 ppm HFC 134a for 13,52, and104 weeks elicited no effect on clinical condition, growth,and survival, or on a variety of hematological, clinical chemistry,and urinary parameters. Treatment-related pathological changeswere seen only at study termination at 2 years and were confinedto increased incidence of Leydig cell hyperplasia and adenomain male rats exposed to 50,000 ppm. The tumors, which were alsoseen in control animals, were benign and not life-threatening.A battery of in vitro and in vivo tests gave no evidence ofgenotoxic activity. With exposure to pregnant rabbits, the onlytreatment-related effects were of minimal maternal toxicityat high exposure concentrations; there were no effects on fetaldevelopment. It is concluded that HFC 134a is of very low toxicityand should be an acceptable alternative to CFCs.     

Nonadditive Developmental Toxicity in Mixtures of Trichloroethylene, Di(2-ethylhexyl) Phthalate, and Heptachlor in a 5x5x5 Design

In order to identify nonadditive effects on development, threecompounds were combined using five dosages of each agent (a5x5x5 full-factorial design). Trichloroethylene (TCE), di(2-ethylhexyl)phthalate (DEHP), and heptachlor (HEPT), in corn oil, were administeredby gavage to Fischer-344 rats on Gestation Days 6–15.Dose levels were 0, 10.1, 32, 101, and 320 mg/kg/day for TCE;0, 24.7, 78, 247, and 780 mg/kg/day for DEHP; and 0, 0.25, 0.8,2.5, and 8 mg/kg/day for HEPT. The dams were allowed to deliverand their pups were weighed and examined postnatally. Maternaldeath showed no main effects but DEHP and HEPT were synergistic.For maternal weight gain on Gestational Days 6–8, maineffects for all three agents were observed, as well as TCE-DEHPsynergism, and DEHP-HEPT antagonism. Maternal weight gain onGestational Days 6–20 adjusted for litter weight showedmain effects for TCE and HEPT, but no interactions. Main effectsfor all three agents were evident for full-litter resorptionsand prenatal loss. The HEPT main effects were unexpected andwere interpreted as reflecting potentiation by HEPT of the otheragents. For full-litter loss, the TCE-HEPT and DEHP-HEPT interactionswere antagonistic, perhaps due to a "ceiling" effect. For prenatalloss, the TCE-DEHP interaction was synergistic. Postnatal lossshowed DEHP and HEPT main effects but no interactions. Analysisof pup weights on Day 1 revealed TCE and DEHP main effects andDEHP-HEPT antagonism; on Day 6, DEHP and HEPT main effects,DEHP-HEPT antagonism, and TCE-DEHP synergism were evident. Microphthalmiaand anophthalmia incidences revealed TCE and DEHP main effectsbut no interactions. This extensive examination of a full-factorialdesign elucidates the complexities of studying and interpretingmixture toxicity. The data are available for further analysis.     

The acute cardiovascular actions of intravenous thyrotrophin releasing hormone (TRH) in man are mediated by non-catecholaminergic mechanisms

1. Intravenous bolus doses of thyrotrophin releasing hormone (TRH, 50–1000 μg) caused statistically significant, non-dose dependent and transient rises in blood pressure, heart rate and plasma catecholamines in healthy young males.
2. Mean peak incremental rises in systolic blood pressure (mean ± s.e. mean) following 50, 200 and 500 μg TRH were 14.3 ± 2.9 mmHg, 15.7 ± 3.2 mmHg and 17.1 ± 3.9 mmHg respectively (all P < 0.05 vs placebo). Mean incremental rises in heart rate for the three doses of TRH were 8.2 ± 2.2 beats min⁻¹, 7.1 ± 1.8 beats min⁻¹, and 1O.7 ± 2.9 beats min⁻¹ respectively (all P < 0.05 vs placebo).
3. Following the 50 μg and 1000 μg doses of TRH, plasma noradrenaline and adrenaline rose significantly (P < 0.05) between 4 and 8 min. Mean ± s.e. mean incremental plasma noradrenaline rise following 50, 200 and 1000 μg TRH were 0.4 ± O.13 nmol 1⁻¹, 0.37 ± 0.21 nmol 1⁻¹ and 0.41 ± 0.18 nmol 1⁻¹ respectively. Mean ± s.e. mean incremental rise in adrenaline for the 50, 200 and 1000 μg dose were 0.13 ± 0.04 nmol 1⁻¹, 0.08 ± 0.03 nmol 1⁻¹, and 0.11 ± 0.05 nmol l⁻¹ respectively.
4. Following administration of the ganglion blocking drug pentolinium (5 mg) the incremental systolic blood pressure and heart rate rises following 500 μg TRH alone 16.6 ± 2.8 mmHg and 1O.4 ± 3.1 beats min⁻¹ respectively.
5. The rises in plasma noradrenaline and adrenaline following TRH were attenuated by prior ganglion blockade.
6. α-adrenoceptor blockade with thymoxamine (0.3 mg kg⁻¹ bolus + 0.3 mg kg⁻¹ h⁻¹ infusion), singly and combined with intravenous propranolol (10 mg i.v. over 10 min), did not alter the pressor or tachycardic effects of 500 μg TRH.
7. In conclusion, although plasma noradrenaline rises following i.v. TRH, suggesting activation of the sympathetic nervous system, this effect is not responsible for the pressor response to TRH, which appears to be due to either a direct vasoconstrictive effect on the peripheral resistance vessels or a direct inotropic/chronotropic effect on the heart.

     

An Analysis of Nasal Irritation Thresholds Using a New Solvation Equation

In the present paper we have developed a quantitative structure-activityrelationship (QSAR) equation for nasal pungency caused by nonreactivevolatile organic compounds (VOCs). Our QSAR was developed uponpreviously published nasal pungency thresholds in anosmics,i.e., patients lacking a sense of smell and thus respondingonly to sensory irritation evoked by trigeminal nerve stimulation.The reported solvation equation, which fits the data with considerableprecision, describes sensory potency in terms of interactionvia electron pairs, dipolarity/polarizability, hydrogen bondacidity and basicity, and hydrophobicity. It correspondinglysuggests relevant physicochemical properties of the biophasewhere the sensory response is brought about. The equation impliesthat in the range of molecular size where nonreactive VOCs canproduce any pungency, transport from the air to the biophasestrictly determines potency. In this respect, the potency ofnasal pungency shares characteristics with the ability of VOCsto cause narcosis and anesthesia.     

A 90-Day Chloroform Inhalation Study in F-344 Rats: Profile of Toxicity and Relevance to Cancer Studies

Composition of diet may influence growth, diseases, tumor rates,and responses to chemical treatment. Since 1980 the NIH–07open formula nonpurified diet has been the selected diet forthe National Toxicology Program (NTP) toxicity and carcinogenicitystudies in rodents. Studies with nonpurified experimental dietswith lower protein and higher fat and fiber than the NIH-07diet indicated that the diet for Fischer-344 (F344) rats inlong-term studies could be modified to decrease the severityof chronic diseases and to decrease/delay the development ofspontaneous tumors. Based on the results of these studies anew open formula nonpurified diet designated as NTP-2000 wasformulated to contain 14.5% protein, 8.5% fat, and 9.5% fiber.Corn, wheat, and wheat middlings contribute to about 60% ofthe ingredients; soybean meal, fish meal, and alfalfa meal arethe additional sources of protein; purified cellulose, oat hulls,and alfalfa meal are the major sources of fiber; and soy oiland corn oil are the major sources of fat in the NTP-2000 diet.The Ca:P ratio and mineral and vitamin concentrations were reformulatedbased on AIN-93 and NRC-95 recommendations. The NIH-07 and theNTP-2000 diets were fed to groups of 6-week-old F344 rats for13 weeks and evaluated for growth patterns, food and water consumptions,hematology and clinical chemistry parameters, and organ weightsand pathological changes. Growth patterns and body weights weresimilar for both diets. Food consumptions were slightly higherand water consumptions were slightly lower for the groups fedNTP-2000 diet. There were no differences in hematological parametersbetween the groups fed the above diets. Serum levels of cholesterol,alkaline phosphatase, and 5' nucleotidase were slightly higherin groups fed the NTP–2000 diet possibly due to higherfat content of this diet. However, the serum triglyceride levelswere slightly lower in groups fed the NTP–2000 diet andit may be related to higher fiber content of the NTP–2000diet. The liver and kidney weights of the groups fed NTP–2000diet were significantly lower possibly due to lower proteincontent of this diet and lower protein consumption associatedchanges in Phase I and Phase II drug metabolizing enzyme systems.The adrenal weights were also lower in groups fed the new diet.The NTP–2000 diet prevented nephrocalcinosis and decreasedthe severity of nephropathy and cardiomyopathy, the common lesionsof F344 rats in 13–week studies. These results indicatethat the NTP–2000 diet is adequate for growth and maintenance of rats and appears to prevent or decrease the severityof diet-associated lesions.     

The Effect of Saline Iontophoresis on Skin Integrity in Human Volunteers: I. Methodology and Reproducibility

This study, conducted in 36 human volunteers, was an evaluationof the effects of saline iontophoresis on skin temperature,irritation, and barrier function. The major objectives wereto assess the effects of low-level ionic currents, to validatethe proposed methodology of assessment, and to establish reproducibilityin repeated saline iontophoresis applications. This was thefirst of a multistage study designed to assess the safety of24-hr saline iontophoresis episodes at selected currents andcurrent densities. Since an iontophoresis patch challenges theskin harrier both by occluding the skin surface and by passingionic current through the skin, the experimental protocol wasdesigned to permit measurement of the contribution of each ofthese processes to the overall response. In this first stagewe investigated the effect of 10 min of current delivery, at0.1 mA/cm² on a 1-cm² area patch and 0.2 mA/cm² on a 6.5-cm²area patch compared to unpowered control patches. Twelve subjectswere tested under each condition on two separate occasions toexamine reproducibility of the response variable measurements.A further 12 subjects were tested once under the 0.2 mA/cm 6.5-cm2condition. Skin irritation was evaluated via repeated measurementsof transepidermal water loss, capacitance, skin temperature,skin color, and a visual scoring system, before the iontophoresisepisode and after patch removal. No damage to skin harrier functionin terms of skin-water loss or skin-water content was detected.Slight, subclinical, short-lasting erythema was observed forboth conditions. Assessment of correlation coefficients showedhighly statistically significant indications of reproducibilityfor all five response variables measured. The experimental design,in combination with a repeated measures analysis, provided clearseparation of the occlusion and ionic current components ofthe iontophoretic patch challenge. Further, the repeated measuresanalysis gave a highly sensitive assessment of skin irritationand resolution after patch removal. We conclude that the experimentalmethodology is appropriate for assessing possible changes inskin integrity resulting from saline iontophoresis under similaroperating conditions for longer durations and for other skinchallenges from which a subclinical response is expected.     

Acrylamide: Dermal Exposure Produces Genetic Damage in Male Mouse Germ Cells

Acrylamide is used extensively in sewage and wastewater treatmentplants, in the paper and pulp industry, in treatment of potablewater, and in research laboratories for chromatography, electrophoresis,and electron microscopy. Dermal contact is a major route ofhuman exposure. It has been shown that acrylamide is highlyeffective in breaking chromosomes of germ cells of male miceand rats when administered intraperitoneally or orally, resultingboth in the early death of conceptuses and in the transmissionof reciprocal translocations to live-born progeny. It is nowreported that acrylamide is absorbed through the skin of malemice, reaches the germ cells, and induces chromosomal damage.The magnitude of genetic damage appears to be proportional tothe dose administered topically.     

Pulmonary Bioavailability and Fine Particle Enrichment of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Respirable Soil Particles

The pulmonary bioavailability of 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) and the enrichment of polychlorinated dioxins (PCDDs)and furans (PCDFs) in fine particles were evaluated to assessthe implications that these factors have on risk and exposureassessments. Respirable subfractions of PCDD-contaminated soilfrom a former 2,4,5-trichlorophenoxyacetic acid manufacturingsite were isolated by chemical dispersion and gravity sedimentation.Analysis of the subfractions revealed that there was a size-dependentenrichment of PCDDs and PCDFs, with smaller particles more highlycontaminated. TCDD was enriched up to 33-fold as compared tounfractionated soil. Soil and laboratory-recontaminated galliumoxide, which served as the positive control, were administeredby intratracheal instillation to female Sprague-Dawley rats.Animals were terminated up to 28 days following treatment andpulmonary bioavailability of TCDD was assessed by hepatic enzymeinduction and TCDD concentration. Enzyme induction was dependenton the duration of exposure with up to 56 and 918% increasesin cytochrome P450 and aryl hydrocarbon hydroxylase (AHH) activity,respectively, following exposure to PCDD-contaminated soil.There was no significant difference in AHH induction betweenanimals which received contaminated soil and those treated withthe positive control. Hepatic concentration of TCDD in soil-exposedrats was 115, 101, and 179% of positive controls at 1, 7, and28 days post-treatment, suggesting that the soil or co-contaminantsinfluenced retention of TCDD in the liver. These data indicatethat the relative pulmonary bioavailability of TCDD on respirablesoil particles is 100% as compared to laboratory-recontaminatedgallium oxide and that PCDDs and PCDFs are highly enriched onrespirable particles. Utilization of these results will reducethe uncertainty and improve the accuracy of envi ronmental riskassessments of PCDDs and PCDFs.