Suppression of Humoral Immune Responses by Dialkylnitrosamines: Structure-Activity Relationships

Suppression of Humoral Immune Responses by Dialkylnitrosamines:Structure-Activity Relationships. KAMINSKI, N. E., JORDAN, S.D., PAGE, D., KIM, B. S., AND HOLSAPPLE, M. P. (1989). Fundam.Appl Toxicol 12,321-332. Comparisons between chemical structureof N, N-dialkylnitrosamine congeners and their ability to alterthe Day 4 IgM antibody response to sRBC, body weights. and organweights of female B6C3F1 mice were investigated. Short-chainnitrosamine congeners were selected for these studies on thebasis of two criteria: (1) congeners wth symmetrical aliphaticchain length [N-nitrosodimethylamine (DMN), N-nitrosodiethylamine(DEN), N-nitrdipropylamine (DPN), N-nitrosodibutylamine (DBN)]and (2) congeners possessing an N-methyl group [N-nitrosomethylethylamine(MEN), N-nitrosomethylpropylamine (MPN), and N-nitrosomethylbutylamine(MBN)]. The immunotoxicity of each congener was evaluated basedon the compound's ability to suppress the in vivo sRBC antibodyresponse following 7 consecutive days of treatment. An ED50dose was calculated, using a linear regression analysis, foreach congener and represents the millimoles of congener perkilogram body weight required to cause a 50% suppression ofthe sRBC response. These studies demonstrated two general trends:(1) those dialkylnitrosamine congeners that possessed an N-methylgroup were most immunotoxic and exhibited comparable ED50 concentrations(42-183 µmol/kg); and (2) dialkylnitrosamine congenerspossessing symmetrical aliphatic chains demonstrated an inverserelationship between aliphatic chain length and immunotoxicpotency—DMN (62 µmol/kg) > DEN (276 µmol/kg)> DPN (467 µmol/kg) > DMN (1557 µmol/kg).Comparisons were also made between the immunotoxic potency ofvarious nitrosamine congeners in the whole animal and theirpotency in an in vitro hepatocyte-spleen cell coculture system.     

Effect of Manganese on the Hepatic Microsomal Mixed Function Oxidase Enzyme System in the Rat

Effect of Manganese on the Hepatic Mixed Function Oxidase EnzymeSystem in the Rat , M. J., and SCHNELL, R. C. (1984). Fundam.Appl. Toxicol. 4, 1009–1018. Experiments were conductedto examine the effect of manganese on the hepatic mixed functionoxidase system in the rat Acute treatment with manganese chloride(1–10 mg Mn/kg, ip) produced a significant prolongationof hexobarbital hypnosis in male rats on Days 2 and 3 followingmetal administration. The threshold dose of manganese to producethis alteration in response was 5 mg Mn/kg and the altered responsereturned to control values by Day 5. The prolonged hexobarbitalhypnosis resulted from Mn inhibition of the hepatic microsomalmixed function oxidase system, the activity of which was assessedusing aniline (23%), ethylmorphine (26%), and hexobarbital (27%)as substrates. Manganese treatment also produced significantlyreduced levels of cytochrome P-450 (23%) and b₅ (21%), but thesubstrate-induced spectral binding of all three substrates wasnot altered significantly by Mn when expressed as A per nanomoleof cytochrome P-450. The activity of NADPH cytochrome c reductasewas also significantly decreased (25%) by Mn treatment Followingthe in vitro addition of Mn in concentrations ranging from 1x 10^–6 to 1 x 10^–3 M Mn to microsomes derived fromnaive rats, there was no decrease in the metabolism of anilineor hexobarbital or cytochrome P-450 levels. Significant inhibitionin ethylmorphine metabolism was observed with Mn concentrationsof 1 x 10^–4 m and greater. These experiments indicatethat acute Mn treatment can alter drug response as the resultof decreased hepatic biotransformation which occurs by an indirectmechanism.     

In Vivo and in Vitro Percutaneous Absorption and Skin Decontamination of Arsenic from Water and Soil

The objective was to determine the percutaneous absorption ofarsenic-73 as H₃A_sO₄ from water and soil. Soil (Yolo County65-California-57-8) was passed through 10-, 20-, and 48-meshsieves. Soil retained by 80 mesh was mixed with radioactivearsenic-73 at a low (trace) level of 0.0004 µg/cm² (microgramsarsenic per square centimeter skin surface area) and a higherdose of 0.6 µg/cm². Water solutions of arsenic-73 at alow (trace) level of 0.000024 µg/cm² and a higher doseof 2.1 µg/cm² were prepared for comparative analysis.In vivo in Rhesus monkey a total of 80.1 ± 6.7% (SD)intravenous arsenic-73 dose was recovered in urine over 7 days;the majority of the dose was excreted in the first day. Withtopical administration for 24 hr, absorption of the low dosefrom water was 6.4 ± 3.9% and 2.0 ± 1.2% fromthe high dose. In vitro percutaneous absorption of the low dosefrom water with human skin resulted in 24-hr receptor fluid(phosphate-buffered saline) accumulation of 0.93 ± 1.1%dose and skin concentration (after washing) of 0.98 ±0.96%. Combining receptor fluid accumulation and skin concentrationgave a combined amount of 1.9%, a value less than that in vivo(6.4%) in the Rhesus monkey. From soil, receptor fluid accumulationwas 0.43 ± 0.54% and skin concentration was 0.33 ±0.25%. Combining receptor fluid plus skin concentrations gavean absorption value of 0.8%, an amount less than that with invivo absorption (4.5%) in the Rhesus. These absorption valuesdid not match current EPA default assumptions. Washing withsoap and water readily removed residual skin surface arsenic,both in vitro and in vivo. The partition coefficient of arsenicin water to powdered human stratum corneum was 1.1 x 10⁴andfrom water to soil it was 2.5 x 10⁴. This relative similarityin arsenic binding to powdered human stratum corneum and soilmay indicate why arsenic absorption was similar from water andsoil. This powdered human stratum corneum partition coefficientmodel may provide a facile method for such predictions.     

Developmental Toxicity of N-Methylformamide Administered by Gavage to CD Rats and New Zealand White Rabbits

N-Methylformamide (NMF) is a metabolite of dimethylformamide(DMF), a solvent with wide applications in the chemical industry.The potential developmental toxicity of NMF was evaluated inCD rats and New Zealand white rabbits. Pregnant rats and rabbitswere dosed once daily by gavage on Gestation Days 6–15and 6–18, respectively. Doses for rats were 0, 1, 5, 10,or 75 mg/kg; doses for rabbits were 0, 5, 10, or 50 mg/kg. Cesareansections were performed on rats and rabbits on Gestation Days20 and 29, respectively. No treatment-related maternal deathsor clinical signs occurred in either species. Body weight gainand food consumption were depressed in rats given 75 mg/kg andrabbits given 50 mg/kg. Fetal viability was reduced at 75 mg/kgin rats and at 50 mg/kg in rabbits. In rats, a significant increasein the incidence of malformations including cephalocele andstern-oschisis was observed in fetuses from the 75 mg/kg group.In addition, a developmental delay was indicated by reductionof fetal weight and by a significant increase in the occurrenceof incomplete ossification of various skeletal structures. Inthe rabbit, fetal body weight was reduced at 50 mg/kg. Malformationsobserved at 50 mg/kg included gastroschisis, cephalocele, domedhead, flexed paw, and skull and sternum anomalies. The lowest-observed-adverse-effectlevels for maternal and developmental toxicity in the rat andrabbit were 75 and 50 mg/kg, respectively. The no-observed-adverse-effectlevel for maternal and developmental toxicity in the rat andrabbit was 10 mg/kg.     

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.