Prenatal exposure to marihuana and tobacco during infancy, early and middle childhood: Effects and an attempt at synthesis

Prenatal exposure to marihuana and tobacco during infancy, early and middle childhood: Effects and an attempt at synthesis

Rook of Absimcts - EURCWOX 94 Applkation of Benchmark Dow Risk Assessment Methodology to Developmental Toxlclty PM.D. Foster, T.A. Auton. Zeneca C...

275KB Sizes 2 Downloads 10 Views

Rook of Absimcts

-

EURCWOX

94

Applkation of Benchmark Dow Risk Assessment Methodology to Developmental Toxlclty PM.D. Foster, T.A. Auton. Zeneca ClL Macclesfield. Cheshire, UKSKlO4TJ In tggt, ti US En~mnmentai Protection Agency first signailed its intention to utilize Benchmark dose risk techniques in the De~lopmental Toxicity Risk Assessment Guidelines. Subs~uen~~ similar intent has been notified in the draft Guidefines for the Risk Assessment of Repmducti~ Toxicity data, with the overall view that such an approach may be applicable to all non-cancer toxicity endpoints. In developmental toxicity experiments a number of factors need to b8 taken into consideration before attempting benchmark dose calculations as compared to the conventional NOAEL approach. For example. care must be taken in the assessment of potential litter effects (the litter is the unit of such a study) on the data and whether the data are continuous (e.g. foetal body weight) or discontinuous (eg specific or grouped developmental defects were the abnormality is either present or absent). Two examples of the utility of the benchmark dose approach will be inade. Firstly,in the analysis of foetal body weight. where a benchmark dose estimate for agent producing a 5% decrease in mean foetal weight may be calculated from a shift in the distributionof foetal weights in the treated versus control groups, and thus the shape of the foetat weight distribution curve is taken into account. or by converting the data to reflect changes due to treatment in the incidence of “small”pups (ie those towards the extreme of the normal range). The second example involvesstudies conducted on the developmental toxicity of a triazole antifungal. In the first study the agent was shown to be clear& teratogenic. but that a clear NOAEL was not established and therefore necessitated the conduct of a second study Analysis of benchmark dose estimates (eg for % foetuses malfo~ed~ from the first study indicated that these were not significantiychanged when the data from the second study wer8 combined. That is, a good estimate of a Benchmark dose was obtained in the first study and if this estimate was deemed acceptable to Regulatoryauthorities the second study (to determine the iriOAEL)woutd not be required, The Benchmark dose approach has significant scientific and practical advantages over the conventional NOAEL methodology in risk assessments derived from developmental toxicity studies.

Molecular Mimicry of CF&O-Lys by Lipoic Acid II: Lipoic Acid Bearing Proteins as Autoantlgens in Halothane Hepatitis &J&y, V.Koch. J. Gut. Dept of Phanrtacofogy;Biocenter of the Unkfersitg Cti-4O?X ifasel. ~wi~ef/aRd The anesthetic agent halothane is metabolized by P456llEl via an acyl chforide inter~diate, giving rise to triituoroacetylated proteins (~F3~O-prote~s}, whim, in a smalf subset of susceptibfe indi~dua~s, are th~ght to precipitate halothane hepatitis. A monospecific antibody towards No-trifiuoroace~~L-line {CF$O-Lys) recognizes such CigCG-proteins. In unexposed humans (and rats). anti-CF6CO antibody crossreacts with constitutively expressed hepatic proteins of 52 kDa and 64 kDa. The latter was identified as the E2 subunit of the pyruvate dehydrogenase complex (PDC). Its prosthetic group, lipoic acid, was shown to be necessary and sufficient to molecularly mimic CFgCO-proteins (i.e. CF$O-Lys). Additional constitutive proteins bsaring lipoic acid are the E2 subunits of the 2oxoglutarate (OGDC) and the branched chain ketoacid (BCOADC) dehydrogenase complexes, and protein X. a constituent of PDC. all of which were recognized by anti-CFgCO antibody in a manner sensitive to competition by (6RSWpoic acid, Lipoyl-Lysand CF3CO-Lys.Sera of halothane hepatitis patients recognize the E2 subunits of OGDC and BCOADC. and protein X. as autoantigens. A role of these lipoylated autoantigens in the etiology of halothane hepatitis is suggested by the fact that in liver biopsies of 5 out of 7 afflicted patients low levels of the E2 subunit of PDC were detectable by anti-CF3CO antibody In contrast, a~oimmune sera towards the protein matrix of the E2 subunit detect normal levels. indicating an aberrancy in lipoy:~tionof the E2 subunit of PDC in these patients. Key words: halothane; immunotoxici~; autoantigen; autoantibody; pyruvate dehydrogenase

Prenatal Exposure to Marihuana and Tobacco During Infancy, Early and Middle Childhood: Effects and an Attempt at Synthesis PA. Fried. Depamentof

Psychology,Carleton Universitv,Ottawa, Canada

Both marihuana and cigarettes appear implicated, in a differential fashion. in the neurobehaviour of infants and children born to women who used these substances during pregnancy. In a low-risk upper middle class sample, marihuana use was associated. in the newborn, with mild withdrawal symptoms and some autonomic disruption of nervous system state regulation. However, between 6 months and 3 years of age no behavioural consequences of marihuana exposure (once confounding factors were controlled) were noted. At four years of age. although global tests of intel~~ence did not differentiate exposed from no~mar~huana expos8d children, verbal admix and rne~ were associated with in utero marihusna exposure. At five and six years of age these general areas were also noted to be associated with maternal cannabis use as was sustained attention. These areas of neurobehaviorthat

Book of Abstmcts - EUROTOX ‘94 appear affected by marihuana exposure during fetal development are ones that are consistent with the cognitive construct of ‘executive functioning’ which is thought to be a marker of prefrontal lobe functioning. Consistent with the ob;iervations derived from these children is that prefrontal functioning may not be apparent until approximately four years of age and that executive functioning is disassociated from measures of global intelligence. Exposure to cigarettes during pregnancy appears to be associated with neurobehavioural deficits in the auditory domain. In the newborn this is manifested by decreased responsivity to sound and altered auditory habituation. Between the ages of one and 11 years the performance on auditory related tasks (verbal memory, language, auditory processing) were consistently the domains that differentiated the cigarette exposed from the non exposed children, The possible role of the cholinergic mediated efferent auditory system is discussed. Also associated with in utero exposure to cigarettes were general cognitive performance and parental reports and objectively derived measures of impulsivity. The striking degree of consistency over the years (ends strength to the interpretation that the sbservations in childhood have, at least as their partial etiology, the prenatal exposure to cigarettes. However, in interpreting the evidence presented it must be recognized that the alterations in the child’s behaviour may well affect the parenting behaviour. This potential transactional interaction must remain an integral part of drawing conclusions about both marihuana and cigarette’s effects.

Absorption, Metabolism and Excretion of Di-N-Propyl lsoclnchomeronata (MGK 326) in the Rat K.L. Gabriel, S. Selim, F.J.Preiss BiosearchIncorporated. Biological 7&t Center; McLaughlin Gormley fing Company The absorption, metabolism and excretion of MGK 326 was determined in rats administered radiolabeled compound orally. The animals were dosed with a single dose of 100 mgn(g and placed in metabolism cages. Urine and feces samples were collected for seven divs. The dosed radioactivity was excreted predominantly (>90%) in the urine with less than 3% excreted in the feces. No parent compound was found. Blood kinetic data indicate that the compound is very rapidly absorbed with peak blood level of radioactivity at 30 minutes and a half life of 2.75 hours. HPLC analysis of the urine revealed one major and one minor metabolite. The metabolites were characterized by GC/MS. and are the product of the hydrolysis of the ester linkages to form the corresponding acids.

Complement Activation Following Intravenous Admlnistration of Oligonucleotide Phosphorothloate in the Monkey W.M. Galbraith, W.C. Hogson l, PC. Giclas *, PJ. Schechter 3, S. Agrawal 3. APD Cornpan)! Arlington, Virginia; 1Sierra Biomedical Incorporated. Sparks,Nevada; * National Jewish Center for Immunology and Respiratoty Medicine, Denver Colorado; 3 Hybridon, Inc., Worcestec Massachusetts Phosphorothioate analogs of oligonucleotides have been studied extensively in the development of antisense oligonucleotide-based therapeutic agents. Bolus intravenous injection of phosphorothioate oligonucleotides is well tolerated in mice, rat and dog. However, monkeys respond to rapid intravenous injection with hypotension ano occasionally death. Rapid intravenous infusion of a 25-mer phosphorothioate oligonucleotide in the monkey produced transient decreases in peripheral total WBC and neutrophil counts. This is followed by a prolonged decrease in art& rial blood pressure. These effects are dose- and infusion rate-dependent and can be avoided by administration of the drug by slow intravenous infusion. Similar hemodynamic effects, produced with rapid intravenous infusion of other phosphorothioate oligonucleotide varying in length from 20 to 33-mer, are therefore, not sequence-specific but may be property of phosphorothioate oligonucleotides. The changes in blood pressure were preceded by complement activation with decreased total complement activity and appearance of a C5a split products. If humans prove to be susceptible to the complement activation observed in the monkey with phosphorothioate oligonucleotide. it is likely that these effects can be avoided with by administration via slow intravenous infusion rather than by bolus administration.

Investigation of the Aquatic Toxicity Profile of Two Carbamate Pesticides D. Gallo’ a.P Ciliutti l, M.F. Mariani l, A. Merendino * . ’ Department of Toxcologv.Research ToxicologyCentre S.p.A., Rome, Italy; * Department of Analytical Chemist&zResearch fixicology Centre S.p.A., Rome, Italy Environmental risk assessment of industrial and agricultural chemicals requires knowledge of their distribution, fate and toxicity to non-target organisms. Two carbamate pesticides (Carbaryl and Aldicarb) have been investigated as part of a validation programme of the aquatic toxicity tests required under current chemical notification and registration schemes.