A 6-Month Multispecies Inhalation Study with Maleic Anhydirde

A 6-Month Multispecies Inhalation Study with Maleic Anhydride.SHORT, R. D., JOHANNSEN, F. R., AND ULRICH, C. E. (1988). Fundam.Appl. Toxicol. 10, 517–524. This study was initiated toassess the safety of atmospheres containing maleic anhydride.Accordingly, rats (15/sex/group), hamsters (15/sex/group), andmonkeys (3/sex/group) were treated 6 hr a day 5 days a weekfor 6 months. Atmospheres were generated by subliming maleicanhydride and were monitored using Tenax collection columnsand gas chromatography to detect total maleic; i.e., maleicanhydride plus maleic acid. The mean analytical concentrationswere 0, 1.1,3.3, and 9.8 mg/m³ of total maleic. Dose-relatedsigns of nasal and ocular irritation were observed at each testlevel in all three species; signs included discharge, sneezing,gasping, and coughing. No significant treatment-related mortalitywas observed in any species. While reduced weight gains wereobserved only in mid- and high-dose rats, their terminal bodyweights were greater than 90% of control values. No treatment-relatedeffects were observed in hematology. clinical chemistry, urinalysis,and pulmonary function tests. Although microscopic evaluationof tissue revealed evidence of nasal irritation in all species,there was no evidence of systemic toxicity which was directlyattributed to maleic anhydride. While the results of this studysupport the current ACGIH TLV and OSHA PEL of 1 mg/m³ regardingsystemic toxicity, continuous exposure at this level duringthe day may produce some signs of irritation.     

LONGEVITY AMONG ETHNIC GROUPS IN ALCOHOLIC LIVER DISEASE

As part of a multicenter V.A. Cooperative Study, 437 male veteranswith varying stages of alcoholic liver injury were followedover a 4.5 year period. Their ethnic distribution consistedof 256 Caucasians, 109 black Afro-Americans, 63 Puerto RicanHispanics, and 9 Native American Indians. Survival analysesrevealed significant differences between groups (P = 0.0002):66% of Afro-Americans were still living at 42 months; Caucasianswere intermediate with 40% survival; and only 28% of Hispanicswere alive. The number of Native American Indians enrolled wastoo small to draw conclusions but none of those enrolled survivedbeyond 24 months. Survival regression analysis of 30 clinical,laboratory, histologic and nutritional parameters, revealedthe following significant risk factors: clinical severity (P< 0.0001), histologic severity (P < 0.0001), race (P =0.001), age (P = 0.002), BUN (P = 0.01) and ALT (P = 0.02).These analyses indicated that ethnicity, independent of othervariables, is significantly associated with outcome from thedisease.     

Inhibition of the Mixed Lymphocyte Culture Response by Antibody Following Successful Human Renal Transplantation

Immunoglobulin G, appearing after several months in the serum of a recipient of a successful kidney transplant from a closely matched sibling donor, was demonstrated to progressively inhibit unidirectional mixed lymphocyte cultures when donor lymphocytes were used either in responding or stimulating cell populations. The active recipient IgG had no effect in cultures in which donor cells were not used, nor did IgG obtained from other individuals show nonspecific inhibitory effects on cultures containing donor cells. It is suggested that the MLC inhibitory immunoglobulin may serve an immunoregulatory function after renal transplantation.     

Acute Inhalation Toxicity of Aliphatic (C1-C5) Nitrites in Rats

Acute Inhalation Toxicity of Aliphatic (C₁–C₅) Nitritesin Rats. KLONNE, D. R., ULRICH, C. E., WEISSMANN, J., and MORGAN,A. K. (1987). Fundam. Appl. Toxicol. 8, 101–106. The 4-hrinhalation LC50 was determined for methyl-, ethyl-, n-propyl-,n-butyl-, isobutyl-, and isopentyl nitrite in Sprague-Dawleyrats. LC50 values were 176, 160, 300, 420, 777, and 716 ppm,respectively. The dose-mortality curves were characterized byextremely steep slopes. Toxic signs observed during exposureincluded cyanosis, prostration, and rarely, convulsions. Therewere no effects of exposure on body weight gain during a 14-daypostexposure observation period. Signs of pulmonary hemorrhagewere apparent in rats which died during exposure but were muchless prominent in rats sacrificed at study termination. No animalsdied after cessation of exposure, and rapid recovery was apparentafter exposure. Concentration x Time (CT) relationships suggestedthat the actual concentration was more important than the "dose"in determining the lethal effects of inhalation exposure tonitrites. Because of the extremely steep dose-mortality curves,the aliphatic nitrites are more hazardous than the LC50 valueswould indicate.     

Neurotoxicity Evaluation of N,N-Diethyl-m-toluamide (DEET) in Rats

The neurotoxic potential of N,N-diethyl-m-toluamide (DEET) wasevaluated following acute oral administration or following multigenerationplus chronic dietary administration to the rat. For the acutestudy, rats were administered undiluted DEET at dose levelsof 50, 200, or 500 mg/kg by gavage. A dose level of 500 mg/kgwas considered to be the highest practical dose that could beevaluated in this study based upon observations of overt toxicityat 500 mg/kg and mortality at 1000 mg/ kg in a dose range-findingstudy. The two measures of neurotoxicity evaluated in the acutestudy were functional observational battery (FOB) and motoractivity measurements. An apparent treatment-related effectin thermal response time (increased) was noted for both sexes1 hr after dosing at the 500 mg/kg dose level. A questionableeffect on rearing activity (decreased) also was noted at thesame dose level. For the multigeneration plus chronic dietaryadministration study, rats were administered DEET at dietaryconcentrations of 0, 500, 2000, or 5000 ppm continuously overtwo generations and then chronically for 9 months. A dietaryconcentration of 5000 ppm meets the criteria for a maximum tolerateddose (MTD) based on traditional chronic toxicology assessments.Evaluations included FOB, motor activity, discriminative acquisitionand reversal in an Mmaze, acoustic startle habituation, passiveavoidance acquisition and retention, and microscopic examinationof central and peripheral nervous tissue. The only effect thatwas considered to be possibly treatment-related was a slightincrease in exploratory locomotor activity at the 5000 ppm doselevel. Based on the results of these studies, the nervous systemdoes not appear to be a selective target when DEET is administeredto rats either as a single oral dose at high dose levels orchronically at the MTD.     

Subchronic Toxicity of Cupric Sulfate Administered in Drinking Water and Feed to Rats and Mice

Subchronic Toxicity of Cupric Sulfate Administered in DrinkingWater and Feed to Rats and Mice. HÉBERT, C. D., ELWELL,M. R., TRAVLOS, G. S., FITZ, C. J., AND BUCHER, J. R. (1993).Fundam. Appl. Toxicol. 21, 461–475. The effects of acute poisoning by cupric sulfate in a numberof species are well known; however, the effects of chronic low-levelingestion of cupric sulfate are less well characterized. Becauseexposure of humans to cupric sulfate may occur through drinkingwater, food, soil, or ambient air, subchronic toxicity studieswere conducted in male and female F344/N rats and B6C3F₁ miceby the drinking water (2-week exposure) and dosed feed (2-and13-week exposure) routes. Animals were evaluated for histopathology,clinical pathology, reproductive toxicity, and tissue metalaccumulation, and target organs were examined by a variety ofspecial stains and by electron microscopy to characterize theobserved lesions. In drinking water, cupric sulfate concentrationsof 300 to 100 ppm produced no ill effects, whereas concentrationsof 3000 to 30,000 ppm were lethal to rats and mice within 2weeks. In feed, cupric sulfate concentrations of 4000 to 16,000ppm caused significant reductions in body weight gain in bothspecies in the 2- and 13-week studies. Hyperplasia and hyperkeratosisof the limiting ridge of the forestomach were present in bothspecies in the 2- and 13-week studies. Rats in the dosed feedstudies had a dose-related increase in inflammation in the liverand changes in clinical chemistry parameters which were indicativeof hepatocellular damage and cholestasis. Histologic changesin the kidneys of rats consisted of a dose-related increasein the number and size of eosinophilic protein droplets in theepithelial cytoplasm and the lumina of the proximal convolutedtubules. Droplets were larger and more numerous in males thanin females. Urinalysis results were suggestive of renal tubularepithelial damage. Iron staining of spleens from treated animalsindicated a marked depletion of iron stores in both male andfemale rats, but not in mice, while hematologic and clinicalchemistry alterations in rats in the 13-week study, along withhistologic changes in bone in the 2-week dosed feed study, wereindicative of a microcytic anemia. Cupric sulfate produced noadverse effects on any of the reproductive parameters measuredin rats or mice of either sex. These results indicate that cupricsulfate at high exposure levels is a hepatic and renal toxicant,as well as an inducer of anemia in rodents, with rats more sensitivethan mice following subchronic exposure.     

Reproductive Toxicity of Butylated Triphenyl Phosphate and Tricresyl Phosphate Fluids in F344 Rats

The effects of tricresyl phosphate (TCP) and butylated triphenylphosphate (BTP)-based hydraulic fluid on reproduction were studiedin F344 rats using a modification of the National ToxicologyProgram's Continuous Breeding Protocol. Groups of breeding pairsreceived single daily oral doses of an equal volume of either0, 0.6, 1.0 g BTP/kg or 0.4 g TCP/kg in sesame oil or 1.7 gneat BTP/kg for up to 135 days. A naive control group allowedto breed, but not dosed or handled daily, demonstrated thatdaily dosing and handling of the rats had no effect on reproduction.The fertility index and number of litters born were significantlydecreased in rats exposed to 1.0 and 1.7 g BTP/kg and 0.4 gTCP/kg. The number of pups per litter was significantly decreasedin the TCP group. A crossover mating experiment using 0.4 gTCP/kg/day and 1.0 g BTP/kg/day groups, each mated with vehiclecontrols, demonstrated that TCP caused 100% infertility in malerats but did not affect reproduction in females. BTP causeda significant decline in reproduction in female rats characterizedby low mating and fertility indices, decreased number of litters,and abnormal estrous cycles. Fertility was decreased in theBTP-dosed male rats. Both sexes of rats in the crossover experimentwith TCP and BTP had significant decreases in terminal bodyweights and increases in adrenal gland and liver weights. OnlyTCP-dosed male rats had significantly decreased testicular andepididymal weights. TCP-dosed female rats had increased ovarianweights, while BTP-dosed females had significantly lower uterineweights. The results of this study indicate that BTP and TCPare reproductive toxicants in F344 rats.     

SULPHASALAZINE-INDUCED AUTOIMMUNE ABNORMALITIES IN PATIENTS WITH RHEUMATIC DISEASE

Sulphasalazine is a commonly used second line agent in rheumatoidarthritis (RA) and other inflammatory joint diseases and isreported to be one of the least toxic of this group of drugs.Recently a severe allergic reaction and cases of lupus-likedisease have been described in patients with RA after treatmentwith sulphasalazine. We describe five patients, all with inflammatoryarthropathy who developed cutaneous vasculitis, lupus-like diseaseor atypical serology after exposure to sulphasalazine. Threeof four cases investigated were found to have the slow acetylatorphenotype. These reactions can complicate the diagnosis anddelay discontinuation of the drug. Moreover, present guidelinesfor the diagnosis of drug-induced lupus do not apply to themajority of patients with sulphasalazine-induced lupus. KEY WORDS: Sulphasalazine-induced lupus, Rheumatoid arthritis, dsDNA antibodies, Vasculitis     

Job stress, absenteeism and coronary heart disease European cooperative study (the JACE study): Design of a multicentre prospective study

Background: The motives, objectives and design of a multicentreprospective study on job stress, absenteeism and coronary heartdisease in Europe (the JACE study) is presented in this paper.Some specific gaps in the reviewed literature are explicitlytapped into by the JACE study. Its objectives are i) to comparethe distributions of the Karasek job stress scales for the samebroad categories of occupations in different European countries(in males and females), ii) to study the predictive power ofthe job stress scales and the job strain model for one yearof sickness absence (in males and females) and iii) to studythe predictive power of the job stress scales and the job strainmodel for a three year incidence of coronary heart disease (Inmales only). Methods: In answering these questions, relationsare studied controlling for gender, age, level of education,company size, physical work risks and shift work, as well astraditional risk factors for CHD (i.e serum cholesterol, serumHDL cholesterol, smoking habits and blood pressure). The JACEstudy is a Biomed 1 concerted action. The JACE group consistsof eight participating centres from six countries, i.e. fromBelgium and Sweden (two centres), France, Italy, Spain, Swedenand The Netherlands (each one centre). The coordination of thegroup is in Brussels. The participating centres brought in over15, 000 European workers to test the hypotheses.