Fundamental and Applied

Fundamentaland AppliedToxicology

An Official Journal of the Society of Toxicology

Volume 36, 1997

EditorHENRY d'A. HECK

Associate EditorsRobert E. ChapinDeborah A. Cory-SlechtaAlan R. DahlElaine M. FaustmanJay 1. GoodmanWanda M. Haschek-HockNancy I. KerkvlietH. B. Matthews

Academic PressEditors EmeritiWilliam W. CarltonBernard A. SchwetzPhilip G. Watanabe

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Copyright © 1997 by the Society of Toxicology

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CONTENTS OF VOLUME 36

Number 1, March 1997

SYMPOSIUM OVERVIEW

Immunotoxicity of Medical DevicesKathleen Rodgers, Paal Klykken, Joshua Jacobs, Carmelita Frondoza, Vesna Tomazic, and JudithZelikoff 1

REGULAR ARTICLES

Subacute Toxicity of a Mixture of Nine Chemicals in Rats: Detecting Interactive Effects with a FractionatedTwo-Level Factorial Design

John P. Groten, Eric D. Schoen, Peter J. van Bladeren, C. Frieke Kuper, Job A. van Zorge, and VictorJ. Feron 15

Concentration-Time Relationships for the Effects of Inhaled Trichloroethylene on Signal Detection Behav-ior in Rats

Philip J. Bushnell 30

Isolation and Partial Characterization of Cytoplasmic Granules of LAK Cells from Mice Showing SideEffects of Recombinant Human EL-2

Motonobu Ueno, Isao Yahara, and Kurajiro Kishi 39

Evaluation of Renal Function in Rhesus Monkeys and Comparison to Beagle Dogs Following Oral Adminis-tration of the Organic Acid Triclopyr (3,5,6-Trichloro-2-pyridinyloxyacetic Acid)

C. Timchalk, D. R. Finco, and J. F. Quast 47

Effect of Emulphor, an Emulsifier, on the Pharmacokinetics and Hepatotoxicity of Oral Carbon Tetrachlo-ride in the Rat

U. Y. Sanzgiri and J. V. Bruckner 54

Correlation between Hydrophobicity of Short-Chain Aliphatic Alcohols and Their Ability to Alter PlasmaMembrane Integrity

Susan C. McKarns, Corwin Hansch, William S. Caldwell, Walter T. Morgan, Sarah K. Moore, andDavid J. Doolittle 62

Inflammatory Response of Mouse Skin Exposed to the Very Potent Carcinogen Dibenzo[a,/]pyrene: AModel for Tumor Promotion

George P. Casale, Sheila Higginbotham, Sonny L. Johansson, Eleanor G. Rogan, and Ercole L. Cavalieri 71

Chronic Toxicity and Carcinogenic Evaluation of Diisononyl Phthalate in RatsArthur W. Lington, Michael G. Bird, Robert T. Plutnick, William A. Stubblefield, and Robert A. Scala 79

SHORT COMMUNICATION

Chronic Toxicity and Carcinogenicity Studies of 2-Methylnaphthalene in B6C3F! MiceYoshiaki Murata, Ayumi Denda, Hiroshi Maruyama, Dai Nakae, Masahiro Tsutsumi, Toshifumi Tsujiu-chi, and Yoichi Konishi 90

Number 2, April 1997

Isopropanol Vapor Inhalation Oncogenicity Study in Fischer 344 Rats and CD-I MiceH. Burleigh-Flayer, R. Garman, D. Neptun, C. Bevan, T. Gardiner, R. Kapp, T. Tyler, and G. Wright 95

Effects of Lifetime Lead Exposure in Monkeys on Detection of Pure TonesDeborah C. Rice 112

Benzene-Induced Hematotoxicity and Bone Marrow Compensation in B6C3F1 MiceGeorgia M. Farris, Simon N. Robinson, Kevin W. Gaido, Brian A. Wong, Victoria A. Wong, WilliamP. Hahn, and Rekha S. Shah 119

Evaluation of a Human Corneal Epithelial Cell Line as an in Vitro Model for Assessing Ocular IrritationF. H. Kruszewski, T. L. Walker, and L. C. DiPasquale 130

Biological Markers of Acute Acrylonitrile Intoxication in Rats as a Function of Dose and TimeFrederick W. Benz, Donald E. Nerland, Donna Corbett, and Junyu Li 141

Dose Dependence of Covalent Binding of Acrylonitrile to Tissue Protein and Globin in RatsFrederick W. Benz, Donald E. Nerland, Junyu Li, and Donna Corbett 149

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

Kohji Shimoda, Nobuhiko Wagai, and Michiyuki Kato 157

Perinatal Methanol Exposure in the Rat. II. Behavioral Effects in Neonates and AdultsSander Stern, Christopher Cox, Ray Preston, Archana Sharma, Geoffrey B. Inglis, Marlene Balys, andBernard Weiss 163

Bioavailability of Lead to Juvenile Swine Dosed with Soil from the Smuggler Mountain NPL Site of Aspen,Colorado

Stan W. Casteel, Ross P. Cowart, Christopher P. Weis, Gerry M. Henningsen, Eva Hoffman, WilliamJ. Brattin, Roberto E. Guzman, Matthew F. Starost, John T. Payne, Steven L. Stockham, Stephen V.Becker, John W. Drexler, and James R. Turk 177

ANNOUNCEMENT 188

AUTHOR INDEX FOR VOLUME 36 189

NOTICE

The Subject Index and Chemical Index for Volume 36 will appear in the December 1997 issue as part of thecumulative indexes for the year 1997.

Fundamental and Applied ToxicologyINFORMATION FOR AUTHORS

Fundamental and Applied Toxicology, an official journal of theSociety of Toxicology, publishes scientific articles relating to thosebroad aspects of toxicology that are relevant to assessing the riskof harmful effects from exposure to chemicals, drugs, natural orsynthetic products, or radiation on organisms, tissues, or cells.Manuscripts are considered in all fields of toxicology, includingboth descriptive and mechanistic, as well as interpretive or theoreti-cal investigations that elucidate the risk assessment implicationsof exposure to toxic agents alone or in combination. Studies mayinvolve either experimental animals or human subjects, or they mayfocus on in vitro methods or alternatives to the use of experimentalanimals. Examples of suitable topics include toxicologic studieswhich are structural, biochemical, or functional in nature, investiga-tions of the effects of dose, route of exposure, metabolism, orspecies on toxic responses, and statistical or mechanism-based ap-proaches to risk assessment. Manuscripts may describe either newmethods or new findings. Also published are symposium summa-ries, reviews in toxicology, commentaries on the scientific basisof regulatory policies, viewpoints relevant to the practice or ad-vancement of toxicology, and letters to the Editor.

General guidelines. As a general rule, preference is given tostudies that are both clearly relevant to toxicology and hypothesis-driven. The rationale should be sound, and the experimental designshould be well conceived. Completeness usually requires that dose-response relationships be examined. Manuscripts that primarilydescribe new methods, either experimental or theoretical, shouldprovide examples of their use. When studies involve the use ofexperimental animals, manuscripts should briefly describe the pro-cedures employed for animal care and handling. Experiments thatrequire the use of animals must be conducted in accordance withthe Guiding Principles in the Use of Animals in Toxicology, whichwere adopted by the Society of Toxicology in 1989. A statementof these principles is published in the January issue.

Although sometimes not hypothesis-driven, safety evaluationstudies of new chemicals or drugs may be published if the workis considered complete and the conclusions are unequivocal. Thepre-chronic toxicity profile of a given chemical should be summa-rized in a single manuscript rather than be allocated among separatemanuscripts. Studies that fail to elicit a toxic response (negativestudies) might be acceptable if competently performed. However,due to the need to limit the number of pages published annually,it may be necessary to decline a manuscript that is scientificallysound but is judged to be of limited interest to readers.

A manuscript will be considered inappropriate for publicationif the subject matter is inconsistent with the missions of the journal,or if the findings largely confirm other published research. A manu-script may be declined for reasons of incompleteness, prior publica-tion of portions of the work, inadequate experimental design ormethods, insufficient support for conclusions, or overly specializedsubject matter. In the last case, the editors may recommend submis-sion to a more specialized journal or to a journal in a related field.

Manuscripts are accepted for review with the understanding thatthe same work has not been published, that it is not under consider-ation for publication elsewhere, and that its submission for publica-

tion has been approved by all of the authors and by the institutionwhere the work was carried out; further, that any person cited asa source of personal communications has approved such citation.

Authors submitting a manuscript do so on the understanding thatif it is accepted for publication, copyright in the article, includingthe right to reproduce the article in all forms and media, shall beassigned exclusively to the Society. The Society will not refuseany reasonable request by the author for permission to reproduceany of his or her contributions to the journal.

Submission of manuscripts. All manuscripts (four copies) shouldbe submitted to:

Fundamental and Applied ToxicologyEditorial Office525 B StreetSuite 1900San Diego, California 92101-4495Telephone: (619) 699-6469Fax: (619) 699-6859

Form of manuscript. Four complete copies of each manuscript,in English, should be submitted. All manuscripts must be typewrit-ten, double-spaced (including references) on one side of 8.5 X 11-in. white paper with 1-in. margins on all sides.

Page 1 should contain the article title, the names and affiliationsof all authors, an abbreviated form of the title (not to exceed 40characters including letters and spaces), and the name and completemailing address (and telephone number if possible) of the personto whom all correspondence should be sent. The article title shouldbe comprehensive and descriptive: proprietary names must not beused in titles, but may be identified in footnotes.

Page 2 should contain an abstract starting with the title of thepaper, followed by the authors' names and reference to Fundamen-tal and Applied Toxicology; blanks should be left so that the Editormay fill in the volume and page numbers. The abstract will belimited to 250 words but must contain a concise summary of whatwas done, the results obtained, and valid conclusions which aredrawn therefrom. It must mention the compounds or families ofcompounds studied, their actions, and the species of animals. Itmust contain important words which are used as index terms, butnot proprietary names.

Example: Early Effects of Lead on Bone Marrow Cell Respon-siveness in Mice Challenged with Listeria monocyto-genes. KOWOLENKO, M., TRACY, L., AND LAWRENCE, D.

(1991) Fundam. Appl. Toxicol. 17, 75-82.

Introduction. State why the investigation was carried out, noteany relevant published work, and delineate the objective of theinvestigation.

Methods. New methods or significant improvements of methodsor changes in old methods must be described. Methods for whichadequate reference can be cited are not to be described. In theMethods section, authors should draw attention to any particularchemical or biological hazards that may be involved in carrying

out the experiments described. Any relevant safety precautionsshould be described: if an accepted code of practice has beenfollowed, a reference to the relevant standards should be given.

Results. Duplication between the text of this section and materialpresented in tables and figures should be avoided. Tabular presenta-tion of masses of negative data must be avoided and replaced witha statement in the text whenever possible. The statement mustinclude (a) what was done, (b) how it was done, (c) how the datawere analyzed, (d) a measure of variability, and (e) the significanceof the result.

Discussion. This section must relate to the significance of thework to existing knowledge in the field and indicate the importanceof the contribution of this study. Needless detailed recapitulationof the results must be avoided. Unsupported hypotheses and specu-lation should be omitted.

References. Names of authors are to be cited in the text withthe year of publication in parentheses. When there are more thantwo authors use the first author's name followed by et al. Allpapers mentioned in the text must be listed in the reference listand vice versa. References should be listed alphabetically typeddouble-spaced on a separate sheet at the end of the paper with allauthors included. Journal titles should be abbreviated according toChemical Abstracts Service Source Index, 1985. Note the followingstyles for references.

Coulston, F., and Pocchiari, F. (1983). Accidental Exposure toDioxins: Human Health Aspects, pp. 4-15. Academic Press, NewYork.

Juberg, D. R., Webb, R. C , and Loch-Caruso, R. (1991). Character-ization of o,//-DDT-stimulated contraction frequency in ratuterus in vitro. Fundam. Appl. Toxicol. 17, 543-549.

MacFarland, H. N. (1976). Respiratory toxicology. In Essays inToxicology (F. R. Blood, Ed.), Vol. 7, pp. 121-153. AcademicPress, New York.

Footnotes should be identified in the text by superscript Arabicnumerals and cited consecutively throughout the paper. All foot-notes should be listed in order and typed double-spaced on a sepa-rate sheet. Proprietary names of substances and names and ad-dresses of suppliers should be identified in footnotes. If the paperhas been presented orally in whole or in part, the date, and occasionshould be included in a footnote.

Tables must be typed double-spaced on a separate sheet withthe title typed directly above the table. Do not use abbreviationsin the title. The title and footnotes must contain all the informationnecessary to understand and interpret the table without referenceto the text Tables must be numbered consecutively with Arabicnumerals. Footnotes to tables should be identified by superscriptlowercase italic letters and placed at the bottom of the page con-taining the table. Letters should be assigned to table footnotesalphabetically in order of appearance as the table is read horizon-tally, not vertically.

Figures should be numbered consecutively with Arabic numer-als. All legends are to be typed consecutively on a separate sheet.All figures should be planned to fit the proportions of the printedpage (7j x 9 in.; column width, 3.5 in.); wherever possible, figureswill be reduced to single-column width. Lettering on the originalfigure should be of professional quality or generated by high-reso-

lution computer graphics and should be large enough (10-12points) to be legible after reduction of the figure to single-columnwidth (approximately 50 to 60%). Differences in type size withina single figure should be no more than approximately 15%. Free-hand, penciled, or typewritten lettering is not acceptable. Drawingsshould be made with the equivalent of black India ink on tracinglinen, smooth-surface white paper, or Bristol board. Alternatively,high-quality computer graphics may be acceptable. In addition,symbols used to identify points within a graph should be largeenough that they will be easily distinguishable after reduction.Graphs should be plotted with black India ink on blue coordinateor white paper no larger than 8.5 X 11 in. Grid lines that are toshow must be inked in black.

Photographs must be kept to a minimum. Photographs shouldbe glossy prints (5 X 7 or 8 X 10 in.). High-contrast micrographsshould be submitted in quadruplicate. Overlays indicating the partsof the electron micrographs that are to be emphasized must beused. Electron micrographs should be submitted not larger than6.5 X 4.5 in. Magnification should be indicated by a bar on thephotograph.

Illustrations in color will be accepted only if the authors defraythe cost

Index terms suitable for use in the subject index must be submit-ted on a separate sheet. The list should include chemical name,generic name, common name, and may include the proprietaryname of each important substance used in the experiments. Itshould also include biological activity of each substance investi-gated. Terms should elucidate important relationships.

Nomenclature. For styling of isotope, enzyme, and biochemicalnomenclature, consult the extended Instructions to Authors pub-lished in each January issue of Archives of Biochemistry and Bio-physics.

Abbreviations. Units will be in general accordance with the Inter-national System (SI) as adopted by the 1 lth General Conferenceon Weights and Measures. Periods are not used after abbreviations(note exceptions, e.g., in. for inches).

Common abbreviations to be used in this journal are:

mcmmmfxmnmkggmgMgngmlMlmolM

mM(MM

N

CiX

metercentimetermillimetermicrometernanometerkilogramgrammilligrammicrogramnanogrammillilitermicrolitermolemolarmillimolarmicromolarnormalCuriemean

ppmcpmdpmscicim

ipivpoLD50LC50Hz°CsecminhrSDSE

parts per millioncounts per minutedisintegrations per minutesubcutaneousintracutaneousintramuscularintraperitonealintravenousoralmedial lethal dosemedial lethal concentrationhertzcentigradesecondsminuteshoursstandard deviationstandard error

Reprints. A reprint order form will accompany the proofs. Fiftyreprints of each article (without covers) are supplied free of charge.Authors may purchase additional reprints using the form provided.

Communications (Preliminary Reports). Fundamental and Ap-plied Toxicology will accept a limited number of brief reports ofwork that has progressed to the stage at which it is considered thatthe science of toxicology would be advanced if the results weremade available as soon as possible. These reports will be desig-nated "Preliminary Reports." Authors should submit short papersfor this category of publication only when they believe that therapid communication of the results is of the utmost importance toother investigators. Four copies of the manuscript, with a letterrequesting publication as a Preliminary Report, must be submittedand conform strictly to the form and style of the journal. The lengthmust be such that it will require no more than four pages in thepresent format of the journal.

Letters to the Editor. Letters to the Editor will be accepted forpublication subject to Editorial Board approval, provided that thecontent deals with papers published in Fundamental and AppliedToxicology and that the comments are of scientific value. Lettersshould be received within two months of mailing of the journaland should be no longer than 250 words. Introduction of new datawill not be permitted. Each letter will be submitted to the author

of the original paper in order that any reply may be publishedsimultaneously with the letter.

Personal computer disks. Manuscripts may be submitted to Fun-damental and Applied Toxicology on personal computer disks afterthe manuscript has been accepted and after all revisions have beenincorporated onto the disk. Label the disk with the type of computerused, the type of software and the version number, and the diskformat. All tabular material will be typeset conventionally. Artmust be prepared as camera-ready copy; see the section on Figuresearlier in this Information for Authors.

A hard copy printout of the manuscript that exactly matches thedisk file must be supplied. Academic Press will not accept diskswithout accompanying printouts of all files on the disk. File namesmust clearly indicate the content of each file. The manuscript willbe edited according to the style of the journal, and the proofs mustbe read carefully by the author. Disks that are not translatable oreconomical to process will not be used. The publisher reserves theright not to use the disk.

For further information on preparing disks for typesetting con-version, please contact the publisher (Editorial Supervisor, JournalDivision, Academic Press, 525 B Street, Suite 1900, San Diego,California 92101-4495; telephone: (619) 699-6870; fax: (619) 699-6800).

For information about advertising in Fundamental and Applied Toxicology, please con-tact Andrea Cowan, Advertising Coordinator, Academic Press, 525 B Street, Suite 1900,San Diego, California 92101-4495 (telephone: (619) 699-6825, fax: (619) 699-6380).

Two OFFICIAL JOURNALS OF THE

SOCIETY OF TOXICOLOGYdtoticology and

ied PharmacologyToxicologyand AUEditor

Edward BresnickUniversity of Massachusetts MedicalCenter, Worcester

Toxicology and Applied Pharmacology publishes original

scientific research pertaining to action on tissue structure orfunction resulting from administration of chemicals, drugs, ornatural products to animals or humans. Articles address mecha-nistic approaches to physiological, biochemical, cellular, or mol-ecular undemanding of toxicologic/pathologic lesions and tomethods used to describe these responses.

Papers concerned with alternatives to the use of experimentalanimals are encouraged.

Short reviews on timely subjects, communications,announcements, and letters to the editor are also featured.

Database coverage includes Biological Sciences (BIOSIS), ChemicalAbstracts, Current Contents/Life Sciences, Excerpta Medica(EMBASE), Index Medicus (MEDLINE), and Science Citation Index.Volumes 142-147 (1997), 12 issues (including chemical and subject indexes)

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Fundamental aiApplied Toxicol

I Fundamentaland Applied 'Toxicology Editor

Henry d'A. HeckChemical Industry Institute of ToxicologyResearch Triangle Park, North Carolina

Fundamental and Applied Toxicology presents current articlesand reports relating to those broad aspects of toxicology relevantto assessing the risk of exposure of toxic agents (chemicals,including drugs and natural products) to human and other animalhealth.

Present ing Articles on• Methods and results of toxicology studies that are structured,

biochemical, or functional in nature and involve experimentalanimals, humans, or alternatives to the use of animals

• Statistical and mathematical methods of risk assessment andsafety evaluation

Featured SectionsSymposiaShort reviewsMeeting coverageIssues and commentariesLetters to the editor

Research Areas IncludeMethods and equipmentPolicy articles on the practice of toxicologyRegulatory issuesRisk assessmentSafety evaluation

Database coverage includes Current Contents/Life Sciences, ExcerptaMedica (EMBASE), Index Medicus (Medline), and Sri Search.

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TOXFAAT 97 A

Mouse Brain

Keith B.J. FranklinMcGill University Montreal. Quebec Canada

George T. PaxinosJhe University ol New South Wales, Sydney, Australia

The Mouse Brain in Stereotaxic Coordinates u> me lust

atlas in more than 20 years to provide an up-to-date diagram-

matic reference illustrating the coronal plates of the mouse

brain. As in the renowned Academic Press publication, Rat

Brain in Stereotaxic Coordinates, Second Edition, the

stereotaxic accuracy of each section is ensured. The standard

reference marks are repeatedly found in the structures, and

the atlas is sectioned with excellent symmetry. The large, easy-

to-use format displays the sections alternately stained for Nissl

substance and for acetylcholinestrase. Comprising 93 clearly

reproduced images and corresponding diagrams, this atlas is a

must reference in >

CoordinatesKEY FEATURES1 Presents 95 high magnification coronal plates of sections 120 microns apart coveringthe mouse brain from the olfactory bulb to the middle level of the medulla

1 Contains stereotaxic grid based on meticulous placement of the fiducials1 Displays greater magnification than that afforded by any of themammalian atlases

• Includes full annotated accompanying diagrams and stereotaxic grid1 Details mammalian neuroanatomy with ensured accuracy

ATLAS BENEFITS

• Based on the flat-skull position, with the bregma. the lambda and themidpoint of the interaural line usable as reference points

• Based on a complete series of sections taken from a single adult male C57BL/I6mouse

• Consists of 93 photographic pbtes and accompanying diagrams with an averagedistance of 120 um between adjacent plates

• Photographs of Nissl-stained sections are alternated withacetylcholinestrase stained sections

• Structures of the mouse brain are delineated in detail matching that ofRat Brain in Stereotaxic Coordinates, Second Edition

• All areas of the brain are depicted except for the lower medulla

Spiral bound: (125.00 (tentative)November 1996, c 304 pp./IS8N: 0-12-266070-6

Order from your local bookseller

or directly from:

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©1996 by Academe Press. Inc. All RigHs Reserved

KLSAJ/TRABS-2I10M

ALCOHOLSPKCH

Steven B- Chin AlcoholSteven B. Chin and

David B. PisonihnJiaiia I iiivn>iL\\ Blo<mtiii<n<jn and Speech

Key Features• Illustrates a unified perspective for

the study of alcohol and speech

T Contains the benefit of years ofresearch on alcohol and speech

• Provides a wealth of research toinvestigators in a wide variety ofdisciplines: medicine, psycholo-gy, speech, forensics, law, andhuman factors

• Demonstrates how alcohol andspeech research applies in apractical situation: the ExxonValdez grounding

T Includes a glossary as well asnumerous tables and graphsfor a quick overview of dataand results

"The book provides a comprehensive review of the effects of alcohol on speech while comparing thevarious theoretical concerns that form this research. A special merit is the truly exhaustive survey ofthe relevant literature which also lakes into account a significant number of studies which werewritten in and on languages other than English... The book thus serves as a single, unifying up-to-date reference source for those interested in speech motor effects evident in the acoustic records,reaction times, speech communication strategies, and perceptual judgments."

—HERMANN J KUNZEL. University of Trier, Budeskriminalamt Wiesbaden. Germany

'Scientifically characterizing the effects of alcohol on speech has important implications, as exem-plified by the case of the Exxon Valdez. Alcohol and Speech will be the classic reference text onthis important intersection between basic science and social issues."

—UNDA S. SOBELL. Nova Southeastern University. Fort Lauderdale. Florida

• I very comprehensive treatise on alcohol and speech using the captain of the Exxon. Valdez as theanecdotal model... The book Li a meld of a broad array of disciplines each of which can contributeIn a fundamental understanding of the specific effects of alcohol on speech...This book is unique."

—ROBERT F. BORKENSTEIN. Indiana University. Bloomington

"Chin and Pisoni bring to the reader a careful and complete assessment of the effects of alcohol onspeech. The result of their scholarship should be of interest to anyone concerned with alcohol andspeech, but the book also is a valuable reference for the general study offorensirs and the effects ofdrugs on human behavior. This book sets a standard for the field and will surely find a secureplace in the scientific and legal literature."

—RAY D KENT. Waisman Center. University of Wisconsin. Madison

Alcohol and Speech serves as a single, unifying reference source for those interested in speech motor effectsevident in the acoustic record, reaction times, speech communication strategies, and perceptual judgments.Written by a linguist and a psychologist, the book provides an analytic orientation toward speech and alcoholwith an emphasis on laboratory -based research in acoustic-phonetics and speech science. It is a comprehensivereview of the effects of alcohol on speech and compares tlie various theoretical concerns which form this research.

Studies of both alcohol and speech have been rare because each field has its own experimental protocols.methodologies, and research agendas. This book fills a long-standing gap and is unique in providing bothbreadth of coverage and depth of analysis. A case study involving the 1989 Exxon laldez oil spill in PrinceWilliam Sound develops some of the legal implications of this research.

January 1997. c. 377 pp.. $49.95 (tentativeVISBN: O-12-172775-O

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