Preliminary toxicity findings in dogs and rodents given the iron chelator ethylenediamine-N,N′-bis(2-hydroxyphenylacetic acid) (EDHPA)

Because of a projected pilot study with EDHPA in Cooley's anemia patients, animal studies with emphasis on reversibility of potential toxic signs were performed. Young dogs were treated iv with 6–18 mg/kg or orally with 30–240 mg/kg for 14 days followed by a 16-day recovery period. Drug-induced emesis, elevated BUN changes in kidney, spleen, and thymus weights diminished during recovery. One deceased dog exhibited nephrotoxicity consisting of tubular necrosis and deposition of the iron-EDHPA complex. The latter was observed in the excreta of survivors but kidney damage was not evident. Atrophy of the spleen and thymus in the deceased dog was consistent with less intense organ weight changes in recovered survivors. In the absence of morphologic changes after recovery, the precise effect on the immune system is unknown. The iv LD50 was 53 mg/kg for rats and mice. No rodent deaths occurred at an oral dose of 6000 mg/kg. An elevated BUN and changes in kidney, spleen, and thymus weights were confirmed in rodents given iv doses of 5–20 mg/kg or oral doses of 150–600 mg/kg for 5 days. It is cautioned that during the use of EDHPA derivatives that the functions of the renal and immune systems be monitored.     

L-Methionine Suppresses Pathological Sequelae of cis-Platinum in the Rat

L-Methionine Suppresses Pathological Sequelae of cis-Platinumin the Rat. BASINGER, M. A., JONES, M. M., AND HOLSCHER, M.A. (1990). Fundam. Appl. Toxicol. 14, 568–577. The pathologicalchanges characteristically observed in the kidney, bone marrow,thymus, spleen, and duodenum of the rat given 12.2 mg/kgofc/5-platinum(CDDP)ipare reduced or eliminated when a CDDP solution containing a20-fold excess of L-methionine to c/s-platinum is administered.L-Methionine was also effective in reducing the renal toxicityinduced by CDDP when given orally 20 min before the iv administrationof 7.5 mg CDDP/kg. L-Methionine did not compromise the efficacyof CDDP when the antitumor activity of the combination of L-methio-nineand CDDP was measured against the Walker 256 carcinosarcomain the rat. No significant reduction in the antitumor activityof the CDDP resulted from the parenteral administration of L-Methioninewhen evaluated against the L1210 murine leukemia. The oral administrationof L-methionine (500 mg/kg) 30 min after the administrationof CDDP has no significant effect on the antitumor activityof CDDP in mice bearing the L1210 murine leukemia. The resultssuggest that L-methionine may have some practical utility inthe control of certain aspects of CDDP toxicity.     

Subchronic Oral and Intravenous (iv) Safety Evaluation and Pharmacokinetics in Rats and Dogs of Ipazilide Fumarate (Win 54, 177-4), an Antiarrhythmic Agent

Ipazilide fumarate (Win 54,177-4) is a chemically novel antiarrhythmicagent that prolongs ventricular refractoriness and possessesantiectopic activity. Subchronic (29 days) nonclinical safetyevaluation of ipazilide was conducted following oral and ivadministration in Sprague-Dawley rats (20–320 mg/kg oraland 1.25–10 mg/kg iv) and 14 and 28 days in beagle dogs(3–30 mg/kg oral and 2.5–20 mg/kg iv). The pharmacokineticparameters of ipazilide indicate that ipazilide is absorbed(t_max 1 hr) in fasted rats and dogs following single and repeatedoral administrations. The apparent elimination half-life inthe two species is approximately 1 hr (except in rats at a dosageof 320 mg/kg), suggesting rapid clearance. Increases in liverweights (rats 320 mg/kg) accompanied by the observation of centrilobularhypertrophy of hepatocytes were considered an expression ofan adaptive metabolic response of the liver to ipazilide andmay be associated with the induction of microsomal enzymes.Duodenal villous atrophy and epithelial hyperplasia (rats, 80and 320 mg/kg) were interpreted to represent an irritant responseto the drug. Local irritation was also observed at the injectionsite in rats and dogs. Dogs tolerated the oral and the iv administrationof ipazilide at dosages of up to 30 and 20 mg/kg, respectively.Despite emesis (oral dogs), which was reduced in frequency followingrepeated treatment over several weeks, plasma levels in treateddogs (i.e., C_max 4–5 µg/ml) were approximately twicethat required to convert spontaneous arrhythmias in the conscious dog model 24 hr after myocardial infarction. Moreover,plasma levels (C_max 6–7 µg/ml) of iv-treated dogswere approximately three times higher than the efficacious levelsin the dog model and did not cause adverse effects except emesis.Electrocardiographic changes (i.e., increased P wave and QRSdurations, and T wave alterations) in dogs were transient andrepresented an extension of the pharmacological effects of ipazilide.In summary, since ipazilide, at multiple therapeutic dosages,was well tolerated in rats and dogs, it may be considered anappropriate drug for clinical evaluation of safety and efficacyin humans as a potential antiarrhythmic agent. The safety profileof ipazilide in clinical trials is currently ongoing.     

Evaluation of the Primary Humoral Immune Response Following Exposure of Male Rats to 17 {beta}-Estradiol or Flutamide for 15 Days

There is a concern that certain industrial chemicals found inthe environment may mimic or antagonize endogenous hormonesand adversely affect the endocrine as well as the immune system.The objective of this study was to determine if exposure ofCrl:CD (SD)BR male rats to 17ß-estradiol (17ß-E2),an estrogen receptor agonist, or flutamide (FLUT), an androgenreceptor antagonist, would significantly alter the primary IgMhumoral immune response to sheep red blood cells (SRBC). Thisstudy was conducted in the context of a male in vivo Tier Ibattery designed to identify endocrine-active compounds (EACs).The Tier I male battery consists of organ weights coupled witha comprehensive hormonal assessment Rats were dosed by the intraperitonealroute for 15 days with vehicle or 0.001, 0.0025, 0.0075, or0.050 mg/kg/day 17ß-E2 or 0.25, 1, 5, or 20 mg/kg/dayFLUT. Six days prior to termination, selected rats were injectedintravenously with SRBC for assessment of humoral immune function.Spleen cell number and spleen and thymus weights were obtained.Serum was analyzed for anti-SRBC IgM antibody by using an enzyme-linkedimmunosorbent assay. At 0.050 mg/kg/day 17ß-E2, meanfinal body and absolute thymus weights were significantly decreasedto 84 and 65% of control, respectively. 17ß-E2 didnot significantly alter spleen weight, spleen cell number, orthe primary IgM humoral immune response to SRBC. The no-observed-adverse-effectlevel (NOAEL) for immune system alteration was 0.050 mg/kg/day17B-E2 since the decrease in absolute thymus weight was judgedto be secondary to the decrements in body weight. In the TierI male battery, responses to 17ß-E2 included decreasedabsolute testis and epididymis weights, decreased relative accessorysex gland unit weights, hormonal alterations (decreased serumtestosterone (T), dihydrotestosterone (DHT), and luteinizinghormone (LH), and increased serum prolactin and E2 levels).The lowest-observed-adverse-effect level (LOAEL) for the reproductiveindices was 0.001 mg/kg/day 17ß-E2 based on the hormonalalterations seen at this level; no NOAEL was established. Exposureto FLUT did not significantly alter mean final body, spleen,or absolute thymus weights, spleen cell number, or the primaryIgM humoral immune response to SRBC. A significant increase(118% of control) in relative thymus weight was observed at20 mg/kg/ day FLUT. The NOAEL for immune system alteration was5 mg/kg/day FLUT based on the increased relative thymus weightsthat were judged to be compound-related. In the Tier I malebattery, responses to FLUT included decreased absolute epididymisand relative accessory sex gland unit weights and hormonal alterations(increased serum T, DHT, E2, and LH, and decreased folliclestimulating hormone levels). The LOAEL for the reproductiveindices was 0.25 mg/kg/day FLUT based on the hormonal alterationsseen at this level; no NOAEL was established. Based on thesedata, the reproductive and not the immune system appears tobe the primary target organ of toxicity in young adult malerats treated with either 17ß-2 or FLUT.     

Subchronic Oral Toxicity of Ethylene Glycol Monobutyl Ether in Male Rats

Subchronic Oral Toxicity of Ethylene Glycol Monobutyl Etherin Male Rats. KRASAVAGE, W. J. (1986). Fundam Appl. Toxicol.6, 349–355. Adult male rats (Crl:COBS CD (SD)BR) weregiven undiluted ethylene glycol monobutyl ether (EGBE) by gavagein doses of 222, 443, or 885 mg/kg/day, 5 days/week over a 6-weekperiod. A dose-dependent decrease, which was statistically significantat the high dose, was seen in body weight gain. Feed consumptionwas also significantly reduced at the 885-mg/kg dose. The mostsignificant toxic effects produced by EGBE were on the red bloodcells including a significant dose-dependent decrease in hemoglobinconcentration. red blood cell counts, and mean corpuscular hemoglobinconcentration. Mean corpuscular hemoglobin and mean corpuscularvolume were increased at all dose levels. Effects secondaryto the red cell effects included increased spleen weights, spleniccongestion, and hemosiderin accumulation in the liver and kidneys.Relative liver weights and serum alkaline phosphatase (443-and 885-mg/kg doses) and serum alanine aminotransferase (885-mg/kgdose) levels were increased. Glucose was significantly reducedin the animals given 885 mg/kg/day. EGBE had no adverse effectson the testes, bone marrow, thymus, or white blood cells.     

Immunotoxicological Characteristics of Sodium Methyldithiocarbamate

This study was conducted to assess immunotoxicological effectsand selected general toxicological effects of sodium methyldithiocarbamate(SMD). Initially, the compound was administered orally to femaleB6C3F1 mice at 300 mg/kg/day for 3, 5, 10, or 14 days. Body,liver, kidney, spleen, and thymus weights were measured. Selectedhematological and bone marrow parameters were examined. Flowcytometric analysis was used to assess changes in lymphocytesubpopulations in the thyrnus and spleen, and production ofantibody-forming cells in vitro was measured. Major effectsincluded decreased thymus weight at all time points; increasedspleen weight after 10 or 14 days of exposure, increased bonemarrow cellularity after 10 or 14 days of exposure, significantdecreases in mature lymphocyte subpopulations which were greaterin the thymus than in the spleen, relatively selective depletionof the major subpopulation of thy mocytes (CD4⁺CD8⁺ and decreasedbody weight. Overall patterns of changes were consistent withthe conclusion that SMD rapidly depletes most CD4⁺CD8⁺ thymocytes,more slowly depletes a smaller number of mature lymphocytesin the thymus and spleen, and induces compensatory and/or detoxicationmechanisms after 10–14 days of exposure. Subsequent experimentswere done to assess selected immune function parameters. SMDat 50–300 mg/kg/day for 7 days caused substantial, dose-dependentsuppression of NK cell activity. No suppression of antibodyproduction in vivo or splenocyte responses to mitogens or allogeneiclymphocytes in vitro was detected. NK cell activity, thymusweight, and CD4⁺CD8⁺ thymocyte numbers were suppressed by dermaladministration of SMD. These results indicate that NK cell activityis significantly decreased by SMD, but mature T and B lymphocyteswhich survive treatment are generally not significantly impairedwith regard to the functions tested. In several experiments,immunological parameters were significantly suppressed in theabsence of a significant decrease in body weight, suggestingthat most of the effects of SMD on the immune system are notsecondary to generalized toxicity.     

Disposition of the Aromatase Inhibitor LY56110 and Associated Induction and Inhibition Studies in Rats, Dogs, and Monkeys

Disposition of the Aromatase Inhibitor LY56110 and AssociatedInduction and Inhibition Studies in Rats, Dogs, and Monkeys.LINDSTROM, T. D., AND WHITAKER, G. W. (1987). Fundam. Appl.Toxicol. 8, 595–604. Compound LY56110 was well absorbedbut slowly excreted in the rat, dog, and monkey. Oral administrationof 5 mg/kg of [¹⁴C]LY56110 (5-bis(4-chlorophe-nyl)methylpyrimidine)to the rat, monkey, and dog resulted in a total excretion of68, 65, and 30% of the radioactivity within 5 days, respectively.Very low urinary excretion was observed in the rat and dog (2%),with fecal excretion being the predominant mode of eliminationin all three species. The plasma radioactivity half-life was49, 41, and greater than 100 hr in the rat, monkey, and dog,respectively. The plasma half-life of parent compound was 18hr in the rat and 10 hr in the dog. LY56110 accounted for only25, 12, and 1% of the plasma radioactivity area under the curvein the rat, dog, and monkey, respectively. High levels of radioactivitywere observed in the target tissues of fat, adrenals, and ovariesof rats. LY56110 induced hepatic cytochromes b₅ and P-450 andcytochrome c reductase in rats after 14 days of oral dosingat 10 mg/kg but not in monkeys after 10 days of oral dosingat 10 mg/kg. The compound was more potent than aminoglutethimideor cimetidine in inhibiting hepatic ethylmorphine and p-nitro-anisoledemethylase activity in vitro. LY56110 also inhibited ethinamate-inducedsleeping time in rats in vivo. The compound induced a reversetype I binding spectrum with rat ovarian microsomes.     

Effect of Acute Propanil Exposure on the Immune Response of C57BI/6 Mice

Effect of Acute Propanil Exposure on the Immune Response ofC57BI/6 Mice. BARNETT, J. B., AND GANDY, J. (1989). Fundam.Appl. Toxicol. 12, 757–764. Propanil is a herbicide thatis used extensively in rice farming to kill weeds without damagingthe rice plant The immunotoxic effects of acute exposure topropanil were determined in adult C57B1/6 female mice exposedintraperitoneally to propanil at doses of 0, 10, 25, 50, 100,200,or 400 mg/kg body wt. One week following exposure, the immunecompetency of the animals was assessed. Contact hypersensitivityresponse (CHR), blastogenic response to T- and B-cell-specificmitogens, and mixed lymphocyte reaction (MLR) were significantlydepressed only in propanil-treated animals at 400 mg/kg. However,the number of splenic antibody-producing cells was also significantlydepressed in a dose-dependent manner at the lower doses of 50,100, and 200 mg/kg. In addition, a significant reduction inthe thymus weight and an increase in absolute and relative spleenweight were also measured in animals treated with 200 and 400mg/kg. The increase in spleen weight also showed a concomitantrise in spleen cellularity. These data indicate that propanilhas a dose-dependent immunotoxic effect on the adult mouse thataffects primarily the humoral response     

4,4'-Methylene-bis(2-chloroaniline) (MOCA): Comparison of Macromolecular Adduct Formation after Oral or Dermal Administration in the Rat

4,4'-Methylene-bis(2-chloroaniline) (MOCA): Comparison of MacromolecularAdduct Formation after Oral or Dermal Administration in theRat. CHEEVER, K. L., RICHARDS, D. E., WEIGEL, W. W., BEGLEY,K. B., DEBORD, D. G., SWEARENGIN, T. F., AND SAVAGE, R. E. JR.(1990). Fundam. Appl. Toxicol. 14, 273–283. The macromolecularbinding of 4,4'-methylene-bis(2-chloroaniline) (MOCA), a suspecthuman carcinogen, was studied in the adult male Sprague-Dawleyrat after both oral and dermal administration. Rats were euthanized1, 3, 7, 10, 14, and 29 days after a single 281 µmol/kgbody wt dose of [¹⁴C]MOCA (oral, 213 µCi/kg; dermal, 904µCi/kg). DNA from various tissues and hemoglobin wereisolated for determination of the time course of MOCA macromolecularbinding. After oral administration adduct formation was rapidwith maximum levels appearing at 24 hr. The 24-hr covalent bindingassociated with the globin was 7.84 pmol/mgglobin (t? = 14.3days). More extensive 24-hr covalent binding was detected forliver DNA with 49.11 pmol/mg DNA (t? = 11.1 days). After dermaladministration of MOCA the major portion of the dose, 86.2%,remained at the application site throughout the study. For theserats the 24-hr covalent binding determined for liver DNA was0.38 pmol/mg DNA (t? = 15.6 days). Although lower levels weredetected after dermal application, similar stability of MOCA-DNAadducts indicates that quantification of such MOCA adducls maybe useful for the long-term industrial biomonitoring of MOCAexposure and for the evaluation of human DNA-MOCA adduct formation,a lesion thought to be associated with the production of cancer.     

Preliminary Toxicity Profile of Arotinoids SMR-2 and SMR-6 in Male B6D2F1 Mice

Preliminary Toxicity Profile of Arotinoids SMR-2 and SMR-6 inMale B6D2F1 Mice. LINDA-MOOD, C, III, GILES, H. D., AND HILL,D. L. (1987). Fundam. Appl. Toxicol. 8, 517–530. Arotinoids,which are analogs of retinoic acid (RA) and retinol (RO) withthe carbon skeleton in a rigid conformation, have more favorabletherapeutic indices relative to all-transRA and al-trans-RO.The purpose of this investigation was to obtain preliminaryin vivo toxicity data on SMR-2 (analog of RO) and SMR-6 (analogof RA), arotinoids with promising activity (ED50's of 20 x 10^–11and 5 x 10^–11 m, respectively; ED50 of RA = 1 x 10^–11m) for reversal of keratinization in tracheal organ culture.A preliminary toxicity study was conducted in male B6D2F1 micewith gavage of retinoids in corn oil (0.01, 0.05, and 0.1 mg/kg/dayof SMR-2 or SMR-6; 1, 5, and 10 mg/kg/day of RA as referencecontrol). Due to lack of toxicity, each dose level for SMR-2and SMR-6 was increased by 4-fold on Day 29 of dosing. The studywas terminated on Day 57. Hypervitaminosis A (weight loss, alopecia,skin scaling, and bone thinning) was induced in the mid- andhigh-dose SMR groups; weight-gain depression was predominantin the high-dose RA group. The SMR compounds were approximately100-fold more toxic, based on weight loss, than RA. In the SMRdose groups with hypervitaminosis A, white blood cell countswere elevated 2- to 4-fold; and there were microscopic lesionsin skin, testes, epididymis, bone, thymus, bone marrow, peripherallymph nodes, spleen, stomach, adrenal, and pituitary. The leuko-cytosiswas attributed to leukopoiesis in spleen and bone marrow, whichmay be due to either a direct effect and/or a secondary responseto a subacute inflammatory reaction in skin. Only peripherallymph node hyperplasia was observed in SMR-2 and RA low-dosegroups. Enlarged thymus, lymph node hyperplasia, leukopoiesisin spleen and bone marrow, elevated alkaline phosphatase withbone hypertrophy, and testicular degeneration were observedin the mid-dose RA group. The results indicate that immune stimulationmay be a primary early response to retinoids and that skin,leukopoietic tissues, reproductive organs, stomach, and boneare primary targets for retinoid toxicity.     

Sublethal Acute Toxicity of Carbosulfan [2,3-dihydro-2,2-dimethyl-7-benzofuranyl(di-n-butylaminosulfenyl)(methyl)carbamate] in the Rat after Intravenous and Oral Exposures

Sublethal Acute Toxicity of Carbosulfan [2,3-dihydro-2,2-dimethyl-7-benzofuranyl(di-n-butylaminosulfenyl)(methyl)carbamate]in the Rat after Intravenous and Oral Exposures. RENZI, B. E.,AND KRIEGER, R. I. (l986). Fundwn. Appl. Toxicol. 6, 7–15.Sublethal toxicity of carcarbosulfan, 2,3-dihydro-2,2-dimethyl-benzofuranyl(di-n-butylaminosulfenyl)(methyl)carbamate,was evaluated in female Sprague-Dawley rats. Erythrocyte acetylcholinesterase(AChE) activity was maximally inhibited 1 min after iv administration(38, 23, and 15% of pretreatment activity after 86, 250, and690 µg/kg, respectively) and recovered by 4 hr. MaximumAChE inhibition (63% of pretreatment activity) was measured45 min after oral dosing (690 µg/kg) and activity recoveredafter 5 hr. Signs included urination, defecation, facial musclefasciculations, salivation, and tremors. Carbosulfan was lesstoxic when given orally. Metabolic activation of carbosulfanto carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranol methylcarbamate)was in vestigated by measuring plasma concentrations 4, 30,and 240 min after iv (80–120 or 620–640 µg/kg)and oral (540–700 or 2030–2190 µ/kg) dosagesof [carbonyl-¹⁴C]carbosulfan. Peak plasma concentrations weremeasured at 4 and 30 min after iv and oral exposure, respectively.Carbosulfan was rapidly activated to carbofuran. Reduction inAChE activity was better correlated (r = 0.97) with plasma concentrationof [carbosulfan + carbofuran] and plasma carbofuran (r = 0.96)than with plasma carbosulfan (r = 0.73). Signs generally occurredwhen AChE activity was less than 65% of pretreatment levels,corresponding to 40 pmol/ml [carbosulfan + carbofuran] in plasma.Based on regression analysis and metabolic studies, both carbosulfanand carbofuran contributed to the observed AChE inhibition;however, carbofuran, a more potent in vitro inhibitor and theusual predominant inhibitor in plasma, was responsible for mostof the erythrocyte AChE inhibition.     

Percutaneous Absorption, Metabolism, and Hemolytic Activity of n-Butoxyethanol

Percutaneous Absorption, Metabolism, and Hemolytic Activityof n-Butoxyethanol. BARTNIK, F. G., REDDY, A. K., KLECAK, G.,ZIMMERMANN, V., HOSTYNEK, J. J., and KUNSTLER, K. (1987). Fundam.Appl. Toxicol. 8, 59–70. A series of studies was conductedto examine the percutaneous absorption, distribution, excretion,and hemolytic activity of n-butoxyethanol (BE). Rats receivinga subcutaneous dose of ¹⁴C-labeled BE excreted the radioactivityin the urine (79%), expired air (10%), and feces (0.5%) within72 hr. Of the organs analyzed, thymus and spleen showed elevatedspecific radioactivities as compared with blood. A percutaneousapplication of BE on rats, under nonocclusive conditions, showed25–29% absorption within 48 hr. Peak blook levels of BEoccurred at 2 hr after application; butoxyacetic acid (BAA)was found to be the major metabolite. Comparison of in vitroskin penetration data showed the following absorption patternof BE: hairless rat >> pig > human skin. Hemolysisand associated hematological changes were noted in the ratswhich received single dermal applications of 260–500 mg/kgof BE. In vitro, BAA showed markedly greater hemolytic abilityon rat erythrocytes than did BE. Human erythrocytes showed nohemolysis when incubated with BE or BAA at concentrations thatare hemolytic to rat erythrocytes. An intravenous dose of 62.5mg/kg of BE does not result in hemolysis or hemoglobinuria inthe rat. The rat may be an animal model with increased susceptibilityto the effects of BE compared with humans because of its rapidpercutaneous absorptive ability and its greater hemolytic sensitivity.     

Evaluation of the Teratogenic Effects of Tri-ortho-cresyl Phosphate in the Long-Evans Hooded Rat

Evaluation of the Teratogenic Effects of Tn-ortho-ciesyl Phosphatein the Long–Evans Hooded Rat. TOCCO, D. R., RANDALL, J.L., YORK, R. G., and SMITH, M. K. (1987). Fundam. Appl. Toxicol.8, 291–297. The developmental toxicity of tri-ortho-cresylphosphate (TOCP) was evaluated in Long–Evans rats. Pregnantrats were treated with 87.5, 175, and 350 mg/kg/day TOCP throughoutorganogenesis from gestation Days 6 through 18 (Day of sperm= Day 0). The highest dose tested (350 mg/kg) was lethal in28% of the dams; no maternal deaths or toxicity were observedin the 87.5 or 175 mg/kg dose groups. There were no significantdifferences noted among the experimental and control groupsfor preimplantation loss or resorption. Fetal weights for bothsexes in the TOCP groups were significantly greater than inthe control group; however, no difference among the TOCP groupswas observed. Malformation rates were too low to warrant statisticalanalysis. Numerous soft tissue and skeletal variations wereobserved in both control and TOCP-treated groups; there wereno significant differences in the frequency of variations amongthe dose groups. The results of this study indicate that TOCPis not teratogenic in the Long–Evans rat.     

A Short-Term Feeding Study with Deoxynivalenol (Vomitoxin) Using Rats

A Short-Term Feeding Study with Deoxynivalenol (Vomitoxin) UsingRats. ARNOLD, D. L., KARPINSKI, K. F., MCGUIRE, P. F., NERA,E. A., ZAW1DZKA, Z. Z., LOK, E., CAMPBELL, J. S., TRYPHONAS,L., AND SCOTT, P. M. (1986). Fundam. Appl. Toxicol 6,691–696.Groups of 25 male and 25 female Sprague-Dawley rats were feddiets containing 0, 0.25, 0.5, or 1.0 mg of deoxynivalenol (DON)/kgbody wt for approximately 9 weeks. Each animal's body weightand feed consumption were measured weekly. Upon terminationof the study, each animal's body, heart, liver, spleen, thymus,and kidneys were weighed. A hematological assessment and a 16-parameterserum evaluation were conducted and 8 animals from each groupwere randomly selected to receive tritiated thymidine iv toassess mitotic activity in the esophagus, jejunum, and spleen.A statistically significant, dose-related decrease in body weightgain was observed for all treated females, but only the malesdosed at 1.0 mg/kg were found to have a treatment-related weightgain suppression. The reduced body weight was attributed toa reduced feed consumption. Reductions that were observed inabsolute organ weights, were not apparent after adjusting forbody weight suppression. No dose-related hematological findingswere found. Serum chemistry changes included increased concentrationsof chloride and decreased concentrations of CO₂ and albumin,but only in the females. No histopathological lesions were attributedto DON treatment, but significant decreases in thymidine labelingoccurred in the spleens and jejunums from the males dosed at1.0 mg/kg.     

Disposition and Elimination of BIOLF-143, an Antiviral Agent, in the Rabbit

Disposition and Elimination of BIOLF-143, an Antiviral Agent,in the Rabbit. ECOBICHON, D. J., BONDZI-SIMPSON, F., COMEAU,A. M., MEKHAEL, K. M., MAJOR, P., AND OGJLVIE, K. K. (1990).Fundam. Appl. Toxicol. 14, 160–166. BIOLF-143, (N-(dimethylamino)methy-lene-9-[[2-hydroxy-l-(hydroxyrnethyl)ethoxy]methyl]guanine),an experimental, purine-based, acyclic nucleoside was administeredby iv or ip injection to adult, male and female, albino NewZealand rabbits in order to determine: (1) the pharmacokineticdisposition, (2) the route and rate of excretion, (3) the biotransformation,and (4) the acute toxicity of the agent. HPLC analysis of bloodplasma concentrations of BIOLF-143 was conducted following ivinjections of 50 or 100 mg/kg and ip injections of 250 mg/kg.Tissue levels of BIOLF-143 were analyzed at 60 min followingan ip injection of 100 mg/kg. Metabolism/excretion studies wereconducted over a 48-hr period following ip injections of BIOLF-143(100 mg/kg). The nucleoside was rapidly distributed in the body,with the dose-dependent, estimated plasma half-life being 21–44min. The drug molecule was not extensively bound to proteins,being quantitatively recovered from plasma (94.4 ± 3.2%)and a variety of tissues (85–100%). The bulk of the drug(80–87%) was recovered in the urine within 48 hr of treatment,with no metabolites or unique, unidentifiable peaks being detectedin HPLC chromatograms. No drug residue was found in feces. Noovert toxicity or untoward signs of latent toxicity were observedin animals receiving acute doses of BIOLF-143 up to 250 mg/kgip. A potential target organ might be the kidney since highlevels of drug residue were detected 60 min post-treatment andthis appeared to be the route of elimination from the body.     

Effects of Chronic Treatment with the Leukotriene D4 Antagonist Compound LY171883 on Fischer 344 Rats and Rhesus Monkeys

Effects of Chronic Treatment with the Leukotriene D4 AntagonistCompound LY171883 on Fischer 344 Rats and Rhesus Monkeys. HOOVER,D. M., BENDELE, A. M., HOFFMAN, W. P., FOXWORTHY, P. S., ANDEACHO, P. I. (1990). Fundam. Appl. Toxicol. 14, 123–130.One-year toxicity studies were done to evaluate potential toxiceffects associated with chronic exposure of rats and monkeysto the leukotriene antagonist LY171883. Rats were fed dietarydoses of 0.0, 0.01, 0.03, or 0.1%, equivalent to approximately0, 5, 15, or 50 mg/kg of body weight/day. Monkeys were givendaily nasogastric gavage doses of 0, 30, 75, or 175 mg/kg ofbody weight. No treatment-related effects occurred in physical,behavioral, ocular, food consumption, or uri-nalysis parametersin either species. Mild dose-related hepatotoxicity occurredin rats given approximately 15 or 50 mg/kg of LY 171883. Thehepatotoxicity was characterized by liver enlargement associatedwith induction of hepatic peroxisomal ß-oxidationand microsomal drug metabolism. Male rats also had hepatocellularfatty change, centrilobular hypertrophy of hepa-tocytes, andincreased levels of serum alanine transaminase and total bilirubin.Other effects in rats included minimal decreases in hematocritvalues, decreases in serum triglycerides and cholesterol, andincreased kidney weight The monkeys tolerated daily oral dosesof LY 171883 up to 175 mg/kg with only minor increases in hepaticmicrosomal enzyme activity and slightly increased liver andkidney weights in males. No effects occurred in monkeys given30 mg/kg. There was no induction of hepatic peroxisomal enzymesor pathologic abnormalities in monkeys treated with LY 171883.The peroxisomal inductive effect was apparently a species-relatedeffect separate from the pharmacologic activity of leukotrieneantagonism.     

In Vivo Interactions of Aluminum with Hepatic Cytochrome P-450 and Metallothionein

In Vivo Interactions of Aluminum with Hepatic Cytochrome P-450and Metallothionein. JEFFERY, E. H., JANSEN, H. T., AND DELLINGER,J. A. (1987). Fundam. Appl. Toxicol. 8, 541–548. MaleSprague–Dawley rats (three per treatment group) were administered0, 2, 10, 20, or 40 mg aluminum per kilogram ip per day for3 days as aluminum chloride in saline. Animals were killed 24hr later. Aluminum was found to inhibit hepatic drug metabolismin a dose-dependent fashion. The lowest dose (2 mg or 75 µmol/kg)had no effect on the parameters measured, whereas the highestdose (40 mg or 1.5 mmol/kg) caused a 52% decrease in cytochromeP-450, a 71% decrease in p-nitrophenetole O-deethylase activity,and a 77% decrease in ethylmorphine N-demethylase activity.Hepatic glutathione levels were unaffected by aluminum, whereasmetallothionein (MT) was induced in both liver and kidney. Thedistribution of endogenous metals normally associated with MTwas altered by aluminum administration. At the highest doseof aluminum (40 mg/kg), zinc levels were increased in livercytosol (154%), while copper levels were unchanged in liver,but decreased in kidney (70%). Aluminum was present in the liverand kidney. Of the aluminum in the liver, less than 5% was inthe cytosol, bound to a MT-like protein. It is concluded thatacute ip administration of aluminum adversely effects hepaticdrug metabolism and that aluminum induces and binds to MT ora MT-like protein.     

Maternotoxicity and Fetotoxicity of an Angiotensin-Converting Enzyme Inhibitor, Enalapril, in Rabbits

Maternotoxicity and Fetotoxicity of an Angiotensin-ConvertingEnzyme Inhibitor, Enalapril, in Rabbits. MINSKER, D. H., BAGDON,W. J., MACDONALD, J. S., ROBERTSON, R. T., AND BOKELMAN, D.L. (1990). Fundam. Appl. Toxicol 14, 461–470. When enalapril,an angiotensin-converting enzyme (ACE) inhibitor, was orallyadministered to inseminated rabbits at dosages of 0.1 to 30mg/kg/day for 13 days in a range-finding study, nephrotoxicity,as measured by elevated serum urea nitrogen concentrations,occurred at 1 mg/kg/day and higher dosages and significant (p 0.05) increases in fetal wastage were observed at dosages aslow as 3 mg/kg/day. Saline supplementation during treatmentprevented this rise in urea nitrogen. Fetal wastage was significantly(p 0.05) increased in the absence of maternotoxicity when saline-supplementedfemales were treated with enalapril at 30 mg/kg/day. A developmentaltoxicity study of enalapril in saline-supplemented rabbits producedno evidence of teratogenicity at 3, 10, and 30 mg/kg/ day. Theperiod of sensitivity of fetuses to the toxic effects of enalaprilwas found to be limited to middle-to-late gestation (GestationalDays 14-27). A single oral dose of enalapril (30 mg/kg) on Day26 of gestation resulted in 100% fetal deaths. On the basisof the work done by Broughton Pipkin el al. [1982, J. Physiol.(London) 323, 415–422] and Broughton Pipkin and Wallace(1986, Brit. J. Pharmacol 87, 533–542), which demonstratedthat the sheep fetus becomes markedly hypotensive when the damis treated with captopril or enalapril during late pregnancy,we believe that the observed fetotoxicity of enalapril in rabbitsis also due to fetal hypotension. On the basis of publishedevidence indicating that the renin-angiotensin system in rabbitsand in humans is not developed until middle-to-late gestation,we believe our results support the premise that incidental exposureto enalapril early in human pregnancy is unlikely to be associatedwith an increased risk of fetotoxicity. However, our resultsand those cited above demonstrate that ACE inhibitors are fetotoxicin late gestation in rabbits and sheep, and should be givenin pregnancy only if the potential benefit justifies the potentialrisk to the fetus.     

Maternal and Developmental Toxicity of Chronic Aluminum Exposure in Mice

Maternal and Developmental Toxicity of Chronic Aluminum Exposurein Mice. GOLUB, M. S., GERSHWIN, M. E., DONALD, J. M., NEGRI,S., AND KEEN, C. L. (1987). Fundam. Appl. Toxicol. 8, 346–357.The present study demonstrated aluminum-induced neurotoxicityin mouse dams and developmental retardation in their offspringfollowing oral exposure to several dose levels during gestationand lactation. Female mice fed aluminum lactate (AL) at levelsof 500 or 1000 ppm in their diet from Day 0 gestation to Day21 postpartum were compared to mice which received a 100 ppmaluminum diet either ad libitum or pair-fed to the 1000 ppmAL group. Dams receiving the 500 and 1000 ppm AL diets showedsigns of neurotoxicity beginning at Days 12–15 postpartumand showed significant weight loss. Offspring showed dose-dependentdecreases in body weight (F = 6.47, p < 0.001), crown-rumplength (F = 1.11, p < 0.0001), and ponderal index (F = 6.90,p < 0.0002), at birth and preweaning. Absolute and relativeliver and spleen weights were lower in pups from the high ALgroups compared to controls (F = 3.34, p < 0.025 and F =15.54, p < 0.001, respectively). Neurobehavioral developmentwas somewhat delayed in aluminum-treated pups, but not in theirpair-fed controls (F = 5.52, p < 0.005). In addition to showingoral toxicity of excess AL during development dose-dependenttoxic effects of parenteral aluminum exposure were demonstratedin pregnant mice which were injected subcutaneously with aluminumlactate solution at 10, 20, or 40 mg Al/kg body wt on Days 3,5, 7, 9, 12, 13, and 15 of gestation. Maternal spleen and liverweights were significantly increased in aluminum treated animals(p < 0.001 and p < 0.05, respectively). Fetal crown-rumplengths were significantly reduced in the 20 mg/kg aluminumgroup (F = 9.79, p < 0.001).     

Pharmacological and Toxicological Properties of Arotinoids SMR-2 and SMR-6 in Mice

Pharmacological and Toxicological Properties of Arotinoids SMR-2and SMR-6 in Mice. LINDAMOOD, C, III, COPE, F. O., DILLEHAY,D. L., EVERSON, M. P., GILES, H. D., LAMON, E. W., MCCARTHY,D. J., SARTIN, J. L., AND HILL, D. L. (1990). Fundam. Appl.Toxicol. 14, 15–29. Studies were conducted to define primarypharmacological and toxicological properties of two arotinoids,SMR-2 and SMR-6, in male B6D2F1 mice. Mice were gavaged dailyfor up to 22 days with retinoids in corn oil (0.1, 0.2, or 0.4mg/kg day SMR-2 or SMR-6 or 2.5, 10, or 30 mg/kg all-trans-retinoicacid as a reference control). Toxicological and biochemicalend-points were assayed after 8, 15, and 22 days. At toxic doses,i.e., those inducing weight loss, morphological changes wereobserved in skin, lymph nodes, spleen, bone marrow, liver, thymus,forestomach, adrenal, bone, and testes. Biochemical alterationsincluded elevated serum alkaline phosphatase, corticosterone,and interleukins–1, –2, and –3. Additionalimmune alterations included increased responsiveness of spleencells to both thymus-dependent and thymus-inde-pendent mitogensand increases in the total number of B cells in the spleen.At doses not inducing weight loss, target organ effects includedthe appearance of plasma cells and infiltration of polymorphonuclearcells in lymph nodes; myeloid cell hypercellularity in bonemarrow, hema-topoiesis in spleen; subacute inflammation in forestomach;and periportal cytoplasmic vacuo-lization in liver. At the lowdoses, SMR-2 resulted in decreased responsiveness of spleencells to mitogens and SM R-6 caused increased responsiveness.SMR-6 also increased interleukin-1 and -2 production at lowdoses. Biochemical effects included reduced activities of liveraryl hydrocarbon hydroxylase (AHH) and soluble brain proteinkinase C. Overall, the results suggest that leukcopoiesis andreduced liver AHH and reduced soluble protein kinase C activitiesare the primary and initial pharmacological and toxicologicaleffects of retinoids.