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.     

Relative Bioavailability of Lead from Mining Waste Soil in Rats

The purposes of this study were to determine the extent of absorptionof lead (Pb) in mining waste soil from Butte, Montana, and toinvestigate the effect of mining waste soil dose (g soil/day)on tissue lead concentrations. Young, 7- to 8-week-old maleand female Sprague-Dawley rats (5/sex/group) were given miningwaste soil that contained 810 or 3908 ppm lead mixed in a purifieddiet (AIN-76) at four different dose levels (0.2, 0.5, 2, and5% dietary soil) for 30 consecutive days. Standard groups includeduntreated controls and dosed feed soluble lead acetate groups(1, 10, 25, 100, and 250 µg Pb/g feed). The test soildose levels bracketed a pica child's soil exposure level andthe lead acetate concentrations bracketed the test soil doselevels of lead. Liver, blood, and femur were analyzed for totallead concentration using graphite furnace atomic absorptionspectroscopy. Clinical signs, body weight, food consumption,and liver weights for test soil and standard groups were similarto control. Tissue lead concentrations from test soil animalswere significantly lower than the tissue concentrations forthe lead acetate group. Relative percentage bioavailabilityvalues, based on lead acetate as the standard, were independentof the two different test soils, dose levels, and sex and wereonly slightly dependent on the tissue (blood> bone, liver).Mean relative percentage bioavailability values of lead in theButte mining waste soil were 20% based on the blood data. 9%based on the bone data, and 8% based on the liver data. Theresults of this study will provide the information needed todetermine the significance of lead exposure from Butte soilsin assessing human health risks as part of the Superfund RemedialInvestigation/Feasibility Study process.     

In Vivo Percutaneous Absorption of Boric Acid, Borax, and Disodium Octaborate Tetrahydrate in Humans Compared to in Vitro Absorption in Human Skin from Infinite and Finite Doses

Literature from the first half of this century report concernfor toxicity from topical use of boric acid, but assessmentof percutaneous absorption has been impaired by lack of analyticalsensitivity. Analytical methods in this study included inductivelycoupled plasma-mass spectrometry which now allows quantitationof percutaneous absorption of ¹⁰B in ¹⁰B-enriched boric acid,borax, and disodium octaborate tetrahydrate (DOT) in biologicalmatrices. This made it possible, in the presence of comparativelylarge natural dietary boron intakes for the in vivo segmentof this study, to quantify the boron passing through skin. Humanvolunteers were dosed with ¹⁰B-enriched boric acid, 5.0%, borax,5.0%, or disodium octaborate tetrahydrate, 10%, in aqueous solutions.Urinalysis, for boron and changes in boron isotope ratios, wasused to measure absorption. Boric acid in vivo percutaneousabsorption was 0.226 (SD = 0.125) mean percentage dose, withflux and permeability constant (K_p) calculated at 0.009 µg/cm²/hand 1.9 x 10^–7 cm/h, respectively. Borax absorption was0.210 (SD = 0.194) mean percentage of dose, with flux; and K_pcalculated at 0.009 µg/cm²/h and 1.8 x 10^–7 cm/h,respectively. DOT absorption was 0.122 (SD = 0.108) mean percentage,with flux and K_p calculated at 0.01 µg/cm²/h and 1.0 x10^–7 cm/h, respectively. Pretreatment with the potentialskin irritant 2% sodium lauryl sulfate had no effect on boronskin absorption. In vitro human skin percentage of doses ofboric acid absorbed were 1.2 for a 0.05% solution, 0.28 fora 0.5% solution, and 0.70 for a 5.0% solution. These absorptionamounts translated into flux values of, respectively, 0.25,0.58, and 14.58     

Effects of Acute Lead Acetate Exposure on Adult Guinea Pigs: Electrophysiological Study of the Inner Ear

The effects on humans of lead acetate exposure may involve thecranial nerves, since vertigo and sensory neuronal deafnesshave been reported in lead workers; however, there exist onlya few reports concerning the dose effects of lead acetate bothon the cochlea and the eighth cranial nerve. The effects oflead acetate on the cochlea and the eighth nerve were investigatedsystematically using cochlear microphonics (CM), wholenerveaction potential (AP), and endocochlear potential (EP) in guineapigs (male albino Hartley). Guinea pigs were injected with 2ml of a 1% solution of lead acetate (20 mg) once a week for1–5 weeks. The threshold of whole-nerve AP (N₁) was elevatedby injection of lead acetate, even 40 mg, and whole-nerve AP(N₁) output voltage decreased after injection of 100mg of leadacetate. On the other hand, no change was observed in CM afterlead acetate injection (100 mg) or in EP after lead acetateexposure (40 mg). The blood concentrations of lead acetate wereas follows (mean): control, 4.5 µg/dl; Expt 1, 80 µg/dl;Expt 2, 126 µg/dl; Expt 3, 142 µg/dl;. We concludethat dysfunction of the eighth nerve is induced by high-doselead exposure, but that lead exposure does not induce electrophysiologicaldysfunction of the organ of Corti and the stria vascularis.     

Bacterial and Human Cell Mutagenicity and Mouse Lung Tumorigenicity of the Oxygenated Polynuclear Aromatic Hydrocarbon Phenalenone

Phenalenone (perinaphthenone) is a major oxygenated polynucleararomatic hydrocarbon (oxy-PAH) atmospheric pollutant formedfrom the combustion of fossil fuels. Mutagenicity of phenalenonewas measured in quantitative forward mutation assays with Salmonellatyphimurium TM677 and metabolically competent human B-lymphoblastoidcell lines (MCL-5 and hlAlv2 cells), and its tumorigenicitywas also assessed in a newborn mouse assay. Phenalenone wasmutagenic in Salmonella in the presence of rat liver postmitochondrialsupernatant (PMS) at a minimum detectable mutagen concentration(MDMC) of 12 /µg/ml, but was not mutagenic in the absenceof PMS at concentrations up to 100 /µg/ ml. Phenalenonewas not significantly mutagenic in either human cell line after28 hr treatment, although mutant fractions were increased bynearly fivefold in hlAlv2 cells (at the tk locus) exposed at30 µg/ml. However, after 72 hr treatment, phenalenonewas mutagenic at the hprt locus in hlAlv2 cells with an MDMCof 3 µg/ml Phenalenone was also tumorigenic in male BLU:Hamice with a lung tumor incidence of 33% 6 months after injectionwith 4.2 mg phenalenone, the highest dose tested. Lung tumormultiplicity in this treatment group was 0.5 tumor/mouse. Noincrease in lung tumors in female mice was observed. Indicesof lung tumor incidence (ED₅₀) and multiplicity (TM_1.0) formale mice were 29.3 and 34.9 µxmol, respectively. Thesedata suggest that phenalenone does not contribute significantlyto the mutagenicity or carcinogenicity of combustion emissionextracts.     

Potentiation of Bromotrichloromethane Hepatotoxicity and Lethality by Chlordecone Preexposure in the Rat

Potentiation of Bromotrichloromethane Hepatotoxicity and Lethalityby Chlordecone (Kepone®) Preexposure in the Rat. Agarwal,A.K. and Mehendale, H.M. (1982). Fundam. Appl. Toxicol. 2:161-167.These studies were designed to provide dose-response relationshipsfor chlordecone (CD) potentiation of BrCCl₃ hepatotoxicity inmale rats using biochemical, functional and histopathologicalparameters. The influence of this interaction on BrCCl₃ lethalitywas also examined. Male Sprague-Dawley rats (175–200g)received a single ip dose of 1, 5,10,15 or 25 µL BrCCl₃/kgfollowing a 15 day dietary pretreatment of 0 or 10 ppm CD. Twentyfour hrs after BrCCl₃ challenge, biliary excretion of phenolphthaleinglucuronide (PG), bile flow, serum transaminases (SGOT and SGPT),serum ICD and OCT were examined as functional and biochemicalindices of hepatic injury. Effect of CD on 48 hr LD₅₀ of BrCCl₃was also examined using the method of moving averages. Withthe exception of 1 µL BrCCl₃/kg dose which had no effect,CD-BrCCI₃ combination resulted in potentiation of hepatotoxicityby all parameters examined. Activity of all the serum enzymeswas elevated in a dose related manner. A dose related decreasein the biliary excretion of PG and bile flow was observed. Theseeffects were more pronounced at the higher doses of BrCCl₃.Extensive centrilobular necrosis was observed in the animalsgiven CD-BrCC₃ combination and the necrogenic effect was moresevere at the doses of 15 µL and 25 µL BrCCl₃/kg.BrCC₃-lethality was increased 5-fold by CD as indicated by thedecreased LD₅₀- The results suggest that CD-induced BrCCl₃ toxicityis manifested both in the form of hepatotoxicity and lethalityand since the hepatic functional status is greatly compromised,the CD potentiatedhepatic failure is related to lethality.     

Immunotoxicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in a Complex Environmental Mixture from the Love Canal

Immunotoxicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in a ComplexEnvironmental Mixture from the Love Canal. SILKWORTH, J. B.,CUTLER, D. S., AND SACK, G. (1989). Fundam. Appl Toxicol. 12,303-312.The organic phase ofthe leachate (OPL) from the Love Canal chemicaldump site contains more than 100 organic compounds including2,3,7.8-tetrachlorodibenzo-p-dioxin (TCDD). The immunotoxicpotential of OPL was determined in two mouse strains which differin their sensitivity to aromatic hydrocarbon (Ah) receptor-mediatedtoxicity. OPL was administered in corn oil in a single oralgavage to male BALB/cByJ (Ah^b/Ah_b) mice (0.5, 0.8, or 1.1 g/kg)and DBA/2J (Ah^b/Ah_b) mice (0.6, 0.9, or 1.3 g/kg). TCDD wassimilarly administered at 0.25, 1.0, 4.0, or 16.0 µg/kg.Two days later all mice were immunized with sheep erythrocytes(SRBC). The antibody response (PFC) and organ weights were evaluated4 days later. OPL produced thymic atrophy and hepatomegaly inboth strains at all dose levels. The PFC/spleen in BALB/cByJmice was significantly reduced at the three doses to 34, 13,and 15%, respectively, of the control response. Serum anti-SRBCantibody levels and relative spleen weights were also reduced.The only immune effect in the DBA/2J mice was a decrease ofthe PFC/spleen to 58% of the control at the highest dose. TCDDdecreased the relative thymus and spleen weights only in BALB/cByJmice. However, TCDD produced hepatomegaly, a decrease in serumantibody, and a decrease in PFC/spleen in both BALB/cByJ andDBA/B mice to 3 and 15%. rspectively, at 16 µg/kg. Thus,the TCDD dose required to cause a 50% suppression (ED50) ofPFC/spleen for the BALB/cByJ and DBA/2J strains was 1.84 and3.89 µg/kg, respectively. The ED50 for OPL was 0.24 g/kgin BALB/cByJ mice. The TCDD concentration in the OPL was estimatedto be 7.6 ppm, which agrees closely with the chemical analysis(3 ppm). The results suggest that the immunosuppression causedby OPL in BALB/cByJ mice was primarily due to TCDD. that thenon-TCDD components of OPL diminished the TCDD immunotoxicityin the DBA/2J strain, and that the thymic atrophy and hepatomegalywere caused primarily by the non-TCDD components of the OPL.     

4,4'-Methylenebis(2-chloroaniline) (MOCA): The Effect of Multiple Oral Administration, Route, and Phenobarbital Induction on Macromolecular Adduct Formation in the Rat

The effect of multiple oral administration of MOCA, a suspecthuman carcinogen, was studied in the adult male rat. As manyas 28 consecutive daily doses of [¹⁴C]MOCA at 28.1µmol/kgbody wt (5 µC1/day) were administered and rats were euthanizedat weekly intervals for 7 weeks. MOCA adduct formation for globinand serum albumin was evaluated by determination of [¹⁴C]MOCAcovalent binding. The covalent binding associated with globinshowed a linear increase over the 28-day exposure period with342 fmol/mg globin 24 hr after the final dose. More extensivecovalent binding was detected for albumin with 443 fmol/mg albuminafter the final dose, but increases were not linear. After cessationof dosing, the albumin adduct levels decreased rapidly (t _1/2=4.6 days) in relation to globin adduct levels (t _1/2 =16.1days). The MOCA-globin adduct t _1/2 is consistent with thatdetermined after a single 281 µmol/kg oral dose of MOCA.Significant differences related to route of administration weredetected for 24-hr globin covalent binding with ip > po >dermal. Distribution of undifferentiated [¹⁴C]MOCA was highestin the liver at 24 hr with tissue levels for liver > kidney> lung > spleen > testes > urinary bladder. Inductionof cytochrome P450 enzymes by administration of phenobarbital(100 mg/kg/day/3 days) resulted in a significant (p < 0.05)increase in MOCA-globin adduct formation detected with 33.5pmol/ mg globin for induced rats versus 13.6 pmol/mg globinfor control rats. Although MOCA-globin and albumin adducts showdiffering stability, quantification of such MOCA adducts maybe useful for long-term industrial biomonitoring of MOCA.     

2,3,7,8-Tetrachlorodibenzo-p-dioxin in Pregnant Long Evans Rats: Disposition to Maternal and Embryo/Fetal Tissues

Prenatal exposue to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)interfereswith fetal development at doses lower than those causing overttoxicity in adult animals. In a multigeneration study (Murrayet al., 1979), female rats that were administered 0.01 µgTCDD/kg/day in their diet did not experience reduced fertility;however, reduced fertility was seen in the F₁ and F₂ generations.Exposure to TCDD during development produces alterations inthe reproductive system of the developing pups, such as delayedpuberty and reduced sperm counts in males (Mably et al., 1992a;Gray et al., 1995) and malformations in the external genitaliaof females (Gray and Ostby, 1995). Therefore, the objectivesof this study were to determine maternal and fetal tissue concentrationsof TCDD that are associated with the adverse reproductive effectsseen by Gray and co-workers. Pregnant Long Evans rats receiveda single oral dose of 1.15 µg [₃H]TCDD/kg on GestationDay (GD) 8 and maternal as well as fetal tissue concentrationsof TCDD were measured on GD9, GD16, and GD21. On GD9, the highestlevel of TCDD localized in the maternal liver (25.1% dose).In addition, the amount reaching all the embryos on GD9 was0.01% of the administered dose, which resulted in a concentrationof 0.02% dose/g . The amount of TCDD reaching the fetal compartment(fetuses + placentas) increased to 0.12% dose/tissue on GD16and 0.71% by GD21. The concentration of TCDD within the fetalcompartment (0.01% dose/g) on GD16 was comparable to that foundin the maternal blood and spleen. Concentrations of TCDD ina single embryo/fetus were 39.6, 18.1, and 22.1 pg/g on GD9,GD16, and GD21, respectively. Estimates of hepatic half-lifeof elimination in pregnant rats suggested that TCDD may be eliminatedfaster in pregnant LE rats. Therefore, measurements of biliaryelimination were made in pregnant and nonpregnant LE rats tocompare rates of metabolism; however, biliary elimination ofTCDD is not affected by pregnancy. In conclusion, this doseadministered during a critical period of organogenesis causesadverse effects on the developing reproductive system of rodents.This dose produced a body burden of 22.1 pg TCDD/g within asingle fetus on GD21. This indicates that low-level TCDD exposureduring the perinatal stage of life can produce adverse effectswithin the developing pups.     

Lead-contaminated soil induced oxidative stress,defense response and its indicative biomarkers in roots of <Emphasis Type="Italic">Vicia faba</Emphasis> seedlings

Seeds of Vicia faba. L were grown in increasing concentrations of lead (Pb)-added soils (0–2,000 mg/kg). After germination of 25 days, roots were harvested to investigate oxidative stress, defense response and indicative biomarkers based upon chemical analyses and biological measurements. The results showed that higher concentrations of Pb-polluted soils led to seedling growth inhibition, indicative of phytotoxicity. O₂^•− and lipid peroxidation were increased with the increase of available Pb in soils and Pb contents in roots, displaying a “J”-shaped dose response curve, whereas H₂O₂ showed a biphasic dose response curve (a consecutive “J”-shaped and inverted “U”-shaped curve). Superoxide dismutase (SOD), guaiacol peroxidase (POD) and ascorbate peroxidase (APX) enzymes were activated by soil Pb, displaying biphasic curves. The upregulated POD and APX enzymes might be major scavengers of excessive H₂O₂ when CAT activities were drastically reduced with the increasing soil Pb. The enhanced glutathione (GSH) and APX activities suggested that GSH-ascorbate cycle also participated in eliminating H₂O₂. Moreover, obvious changes were observed in SOD, CAT and POD isoenzyme patterns, but not in APX except increasing intensities of bands. HSP70 synthesis was significantly induced by extraneous Pb from 125 to 1,000 mg/kg and showed a biphasic curve in this experiment. Comparatively, HSP70 and lipid peroxidation might be more sensitive than other parameters in response to Pb stress, suggesting that these two parameters in the roots might be potential biomarkers for early bioassay of Pb-contaminated soils.     

Effect of Diet on Blood Lead Concentration in the Cynomolgus Monkey

Effect of Diet on Blood Lead Concentration in the CynomolgusMonkey. TRUELOVE, J. F., GILBERT, S. G., AND RICE, D. C. (1985).Fundam. Appl. Toxicol. 5, 588–596. Infant cynomolgus monkeys(Macaca fascicularis) were reared from birth in an infant primatenursery and dosed with lead acetate (2 mg Pb/kg body wt/day)from approximately 100 days of age. The monkeys were switchedfrom an infant formula diet to a diet of primate chow and waterat 460 days of age. Beginning at approximately 935 days of age,various diets were fed in the following order infant formulaplus a restricted amount of primate chow, infant formula only,infant formula plus cellulose fiber, infant formula plus phyticacid, cow's milk, and primate chow plus water. Blood lead contentwas determined throughout the experiment. At 360 days of treatment(approx. 460 days of age) the blood lead concentration was 90µg/dl but decreased to 50 µg/dl within 30 days afterthe diet was changed to primate chow and water. When the monkeyswere 935 days of age the introduction of the infant formulaplus a restricted amount of primate chow had little effect onblood lead concentrations. However, when primate chow was removedfrom the diet so that the monkeys were fed infant formula only,there was a rapid increase in blood lead from approximately40 to 220 µg/dl. The addition of cellulose fiber to theinfant formula had no effect on blood lead concentrations, whereasthe addition of phytic acid caused an abrupt decrease to approximately85 µg/dl. Blood lead concentrations increased to approximately190 µg/dl when cow's milk only was fed and decreased toapproximately 55 µg/dl when the monkeys were returnedto a diet of primate chow and water. In a second experiment,infant monkeys were reared as above and dosed from birth withlead acetate at a rate of 25 µg Pb/kg body wt/day. Themonkeys were switched to a primate chow and water diet at 200days of age and at approximately 900 days of age various dietarychanges were made that were similar to those described above.Although blood lead concentrations were much lower and moreviable than in the 2-mg/kg/day dose group, the data showed apattern similar to those of the higher dose group     

Accumulation of Cd(II) in the CNS Depending on the Route of Administration: Intraperitoneal, Intratracheal, or Intranasal

The uptake and subsequent neuronal transport of certain heavymetals in the olfactory mucosa may be a major means by whichthese compounds gain access to the CNS. To contrast olfactoryversus blood-borne routes of exposure, three groups (n = 4)of adult Long-Evans rats were exposed to solutions of radiolabeledCdCl₂. Exposure was by one of three routes: unilateral intranasalinstillation (IN), intratracheal lavage (IT), or intraperitonealinjection (ip). The dose level for the intranasal route was30 µl of 1 µM CdCl₂ labeled with 1 µCi ¹⁰⁹Cd.For IT and ip, the dose was 30 µl of 1 µM CdCl₂diluted to 300 µl in saline and labeled with 1 µCi¹⁰⁹Cd. Rats were euthanized 24 hr after exposure, tissue sampleswere taken, and radioactivity was counted. Cd levels were lowin the olfactory bulbs of rats exposed either intratracheallyor intraperitoneally. However, in rats intranasally exposed,Cd levels were nearly 40 higher in olfactory bulbs ipsilateralto the exposed side than in those on the contralateral side.With all routes of exposure, Cd levels in brain samples wereonly slightly elevated. These results suggest that for certainairborne toxicants, especially those that are excluded fromthe CNS by the blood-brain barrier, the olfactory system mayprovide a direct route of entry into the CNS.     

Stimulation of Prostaglandin Production by Quinolone Phototoxicity in Balb/c 3T3 Mouse Fibroblast Cells in Vitro

Sparfloxacin (SPFX) and levofloxacin (LVFX) with ultraviolet-A(UVA) irradiation have been reported to induce skin inflammationdue to phototoxicity in Balb/c mice. We examined the productionof arachidonic acid metabolites induced by quinolone phototoxicityin Balb/c 3T3 mouse fibroblast cells in vitro. The cells weresimultaneously treated with SPFX or LVFX at 1,10, or 100 µMand UVA irradiation for 5 min (0.5 J/cm²). They were then culturedin quinolone-free medium for 24 hr, and the concentrations ofprostaglandin E₂ (PGE₂ 6-ketoprostaglandin F₁ (6-keto-PGF₁),and leukotriene B₄ (LTB₄) in the incubation medium were measured.Furthermore, the effect of quinolone photoproducts on the productionof the inflammatory mediators and that of indomethacin on PGE₂level were also examined. Treatment with SPFX at 100 µMplus UVA irradiation markedly increased levels of PGE₂ and 6-keto-PGF₁but not that of LTB SPFX or LVFX alone at up to 100 µM,100 µM SPFX, or 100µM LVFX, or less plus UVA irradiation,or UVA-preirradiated quinolone up to 100µM had no effect.indomethacin even at 0.1 µM completely inhibited the PGE₂elevation induced by 100 µM SPFX with UVA. These resultssuggest that PGs released from dermal fibroblasts in the simultaneouspresence of quinolone and UVA could contribute in part to thedevelopment of skin inflammation in vivo.     

Effects of Soman (Pinacolyl Methylphosphonofluoridate) on Coronary Blood Flow and Cardiac Function in Swine

The effects of soman (pinacolyl methylphosphonofluoridate) oncoronary blood flow, the electrocardiogram, and cardiac functionwere measured in -chloralose-anesthetized swine. Coronary bloodflow (CBF), mean arterial blood pressure (MAP), peak systolicleft ventricular pressure (LVP), maximum rate of left ventricularpressure development (dP/dt_max), cardiac output, and the ECGwere monitored continuously. A dose of 2x LD50 of soman (1 LD50= 4.6 .µg/kg) was given at 1 LD50/min in the femoral vein,which produced an increase in coronary sinus plasma acetylcholine(ACh) from a control of 0.7±0.01 nmol/ml to a maximum314% of control at 15 mm and a decrease in CBF from a controlof 99±13 ml/min/100 g to a minimum 55% of control at15 mm. The increase in ACh in the coronary sinus was significantlycorrelated with a decrease in CBF (r=–0.87, p<0.001).The fall in CBF was accompanied by concomitant decreases inIVP, MAP, and dP/dt_max, with S-T segment elevation and ventricularfibrillation. The increase in coronary sinus acetylcholine concentration was significantly correlated with a 10-fold fall incoronary sinus acetylcholinesterase levels from a control of2.47±0.97 mol acetylcholine hydrolyzed/ml blood/min andwas consistent with the time course for the reduced hemodynamicmeasurements. These studies support the hypothesis that acetylcholineincreases following soman toxicity may decrease coronary bloodflow, thereby initiating ischemic electrocardiographic changesand reducing cardiac function.     

Evaluation of Valproic Acid (VPA) Developmental Toxicity and Pharmacokinetics in Sprague--Dawley Rats

Evaluation of Valproic Acid (VPA) Developmental Toxicity andPharmacokinetics in Sprague-Dawley Rats.BINKERD, P. E., ROWLAND,J. M., NAU, H., and HENDRICKX, A. G. (1988). Fundam Appl. Toxicol.11, 485—493. This study was undertaken to assess the pharmacokinetics and developmental toxicity of the anticonvulsant,valproic acid (VPA), a human teratogen, in Sprague-Dawley rats.Oral administration of 200-800 mg/kg VPA (5-20X human 3 therapeuticdose) from Gestational Days (GD) 8 to 17 resulted in increasingmaternal toxicity at the higher doses with 100% maternal lethalityat 800 mg/kg. Although there was an increased incidence of resorptionsat 600 mg/kg (48 ? 43%) compared to controls (18 ? 24%), itwas not statistically significant. Fetal examination on GD 20revealed dose-dependent fetal growth retardation (p 0.05) asevidenced by decreased fetal weight and length in addition tounderossi-fication of both the axial and appendicular skeleton.The incidence of skeletal defects, including abnormal vertebrae,ribs, and craniofacial dysmorphia, also increased with higherdoses of VPA. Cardiac anomalies observed in the two highesttreatment groups consisted of great vessel malformations withor without associated ventricular septal defects (VSDs). Urogenitaldefects were 3 also noted in the 600 mg/kg group. The plasmaelimination half-life on GD 8 was 1.0 ? 0.3 hr at 200 mg/kgand 2.3 ? 0.7 hr at 600 mg/kg. Maximal concentrations of totaland free drug were 341 ? 18 µg/ml and 181 ? 11 µg/ml,respectively, in the low-dose group and 911 ? 379 µg/mland 542 ? 224 µ%/ml in the high-dose group. No significantchanges in any pharmacokinetic 3 parameters (t1/2, AUC, C_max,t_max) were observed over the 10-day treatment period at eitherdose level.     

Effects of Dexamethasone on Functional and Pathological Changes in Rat Bronchi Caused by High Acute Exposure to Chlorine

We assessed the effects of dexamethasone on functional and histologicalchanges after acute exposure to a high level of chlorine gasin an animal model of reactive airways dysfunction syndrome(RADS). Sprague-Dawley male rats were exposed to 1500 ppm ofchlorine for 5 min and treated with either dexamethasone (dex;300 µg/kg/day) or saline intraperitoneally for 7 days.Lung resistance (R_L), airway responsiveness to inhaled methacholine(MCh), airway wall morphometric measurements, and bronchoalveolarlavage (BAL) cells were assessed over a 2-week period afterexposure. Dex administration significantly attenuated both chlorine-inducedincreased R_L, and chlorine-induced increased responsivenessto methacholine compared with saline: –2.7 ± 6.8%vs 102.3 ± 36.6% change from baseline R_L (P < 0.01)and 2.5 ± 0.6 mg/ml vs 1.2 ± 0.7 mg/ml in theMCh concentration required to double the R_L from baseline (P< 0.01). There was a tendency, albeit nonsignificant, forimprovement in some indices of epithelial injury. Dex significantlyattenuated the postexposure neutrophilic cellular response inBAL 1 day after exposure (15.8 ± 4.9% neutrophils inthe dex group vs 49.8 ± 2.7% neutrophils in the salinegroup) (P 50.001). Our results show that dex administrationhelps maintain pulmonary function, reduces BAL inflammatorycell number, and tends to improve some morphometric airway wallstructure parameters in rats exposed to chlorine.     

Acute, Distribution, and Subchronic Toxicological Studies of Succinate Tartrates

The estimated single-dose oral toxicity (50% lethality) of succinatetartrates (ST) was 2–3 g/kg in rats. ST produced minimalto moderate dermal irritation but no evidence of systemic toxicityin a standard acute percutaneous toxicity test in rabbits. STwas not an eye irritant in a standard rabbit low-volume eyeirritation test ST was not genotoxic in a series of six genotoxicitytests. A 14-day oral gavage study in rats at a dose range of0.05–1.0 g ST/kg/day produced only gastric irritation.The no-observed-effect level (NOEL) for gastric irritation was0.1 g/kg for males and 0.05 g/kg for females. A 28-day percutaneoustoxicity study in rabbits produced minimal to moderate dermalirritation and no adverse systemic effects at a high dose of450 mg ST/kg/day. Single-dose absorption, distribution, andelimination (ADE) studies in male rats showed that 10–15%of an oral dose and 1–3% of a dermal dose were absorbed.Approximately 98% of the orally administered ST was eliminatedas ¹⁴C in urine, feces, or expired CO₂ after 72 hr. Approximately80% of the dermally absorbed ¹⁴C dose was eliminated in urine,feces, or expired CO₂ after 72 hr. In conclusion, no adverseeffects were noted in acute toxicity, genotoxicity, or subchronictoxicity studies conducted with ST.     

Chronic Ingestion of Uranium in Drinking Water: A Study of Kidney Bioeffects in Humans

A study was conducted of the chemical effects on the human kidneyinduced by the chronic ingestion of uranium in drinking water.Subjects were divided into two groups: The low-exposure group,whose drinking water was obtained from a municipal water systemand contained <1 µg uranium/L, and the high-exposuregroup, whose drinking water was obtained from private drilledwells and contained uranium levels that varied from 2 to 781µg/L. Years of residence varied from 1 to 33 years inthe low-exposure group and from 3 to 59 years in the high-exposuregroup. The indicators of kidney function measured in this studyincluded glucose, creatinine, protein, and ß₂-microglobulin(BMG). The markers for cell toxicity studied were alkaline phosphatase(ALP),     

30-Day Oral Toxicity Study of L-Selenomethionine in Female Long-Tailed Macaques (Macaca fascicularis)

Twenty female long-tailed macaques received nasogastric intubationof 0–600 µg/kg-day L-sele-nomethionine for up to30 consecutive days. Selenium ingestion was well tolerated atall dose levels until the second to third week of the studyat which time two animals given 600 µg/kg-day died. Oneanimal from the 300 µg/kg-day group was removed from studyon Treatment Day 19 due to selenium-induced hypothermia. Insome cases, administered doses were reduced at the 300 and 600µg/kg-day levels such that the final time-weighted averagedoses were 0, 25, 62–117, 150, 188–203, and 300µg/kg-day. Six animals at the 188 µg/kg-day levelor greater required nonscheduled fruit and dietary supplementationto prevent their impending demise. As the dose and durationof exposure increased, the incidence of anorexia, gastrointestinaldistress, mucocutaneous toxicity, and frequency of reduced bodytemperature also increased. A dose-dependent reduction in bodyweight was also observed. At the greater doses, disturbancesin menstrual function were evident, and were accompanied bythe absence of serum progesterone concentrations above 1.0 ng/ml,reduced luteal phase lengths, increased intermenstrual intervals,and lowered estrogen excretion. A maximum tolerated dose of150 µg/kg-day L-seleno-methionine for 30 days was identifiedbased on mean body weight reduction, hypothermia, dermatitis,xerosis, cheilitis, disturbances in menstruation, and the necessityof dietary intervention to prevent death at doses of 188 µg/kg-dayor greater.     

Effects of Gadolinium Chloride on the Rat Lung Following Intratracheal Instillation

The metabolic behavior, clearance, and pulmonary effects ofgadolinium (Gd), one of the rare earth elements, were investigatedafter single intratracheal instillation of gadolinium chloride(GdCl₃) in male Wistar rats. There was a dose-related increasein Gd content of lung tissue. Gd content in the supernatantof bronchoalveolar lavage fluid (BALF) did not exceed 5 µgGd/ BALF even at a dose of 100 µg Gd/rat. Gd in the lungtissue decreased very slowly with a biological half-life of136 days at a dose of 50 µg Gd/rat. On the other hand,Gd content in the super natant of BALF was not detectable after31 days. These results suggest that intratracheally instilledGd can be retained in epithelial lining fluid only to a limitedextent as soluble forms and is deposited in the lung tissueprobably in insoluble forms which are metabolized very slowly.Calcium (Ca) content in BALF increased more rapidly than othertoxicological indices such as lactate dehydrogenase activity,protein concentration, and inflammatory cell counts. In thelung tissue, levels of Ca in Gd-instilled groups did not differfrom the control value. Although these data suggest that theorigin of Ca may be blood plasma, biological and/or toxicologicalsignificance of increased Ca is not known. The number of neutrophilsreached the maximum at 12 hr after instillation, indicatingthat Gd has the potency to cause acute lung toxicity. Summarizingthe observation, Gd instilled intratracheally into rats wasdeposited in the lung tissue in nonsoluble forms with an extremelylong half-life, while the metal caused a rapid and selectiveinfiltration of serum Ca before acute lung toxicity.