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Introduction to Toxicologic Pathology

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Abstract

Toxicologic pathology involves microscopic examination of organ and tissue specimens from laboratory animals that have been exposed to candidate drugs, devices, or various chemical or biological agents. The goals are to identify organ system toxicity, dose levels that produce toxicity, and biomarkers of toxicity. A variety of investigative techniques are employed in the detection of histomorphologic alterations, most commonly light microscopic examination of histologic tissue sections and preparation of reports containing subjectively based diagnostic terms and interpretations that convey the identity and anticipated significance of observations. Contemporary clinical pathology evaluations are performed to help identify changes in bodily fluids which may precede and/or accompany histological alterations and further characterize these changes and their adversity. Clinical pathology evaluations also help identify potential clinical biomarkers of xenobiotic-associated tissue damage.

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References

  • Andrade MR, Yee J, Barry P, Spinner A, Roberts JA, Cabello PH, Leite JP, Lerche NW (2003) Prevalence of antibodies to selected viruses in a long-term closed breeding colony of rhesus macaques (Macaca mulatta) in Brazil. Am J Primatol 59(3):123–128. https://doi.org/10.1002/ajp.10069

    Article  PubMed  Google Scholar 

  • Bloom W, Fawcett DW, Raviola E (1994) A textbook of histology. Chapman & Hall, New York

    Google Scholar 

  • Bolon B, Garman RH, Pardo ID, Jensen K, Sills RC, Roulois A, Radovsky A, Bradley A, Andrews-Jones L, Butt M, Gumprecht L (2013) STP position paper: recommended practices for sampling and processing the nervous system (brain, spinal cord, nerve, and eye) during nonclinical general toxicity studies. Toxicol Pathol 41(7):1028–1048. https://doi.org/10.1177/0192623312474865

    Article  PubMed  Google Scholar 

  • Boyce RW, Franks AF, Jankowsky ML, Orcutt CM, Piacquadio AM, White JM, Bevan JA (1990) Sequential histomorphometric changes in cancellous bone from ovariohysterectomized dogs. J Bone Miner Res 5(9):947–953

    Article  CAS  PubMed  Google Scholar 

  • Boyce RW, Paddock CL, Gleason JR, Sletsema WK, Eriksen EF (1995) The effects of risedronate on canine cancellous bone remodeling: three-dimensional kinetic reconstruction of the remodeling site. J Bone Miner Res 10(2):211–221

    Article  CAS  PubMed  Google Scholar 

  • Boyce JT, Boyce RW, Gundersen HJ (2010a) Choice of morphometric methods and consequences in the regulatory environment. Toxicol Pathol 38(7):1128–1133

    Article  PubMed  Google Scholar 

  • Boyce RW, Dorph-Petersen KA, Lyck L, Gundersen HJ (2010b) Design-based stereology: introduction to basic concepts and practical approaches for estimation of cell number. Toxicol Pathol 38(7):1011–1025

    Article  PubMed  Google Scholar 

  • Boyce RW, Varela A, Chouinard L, Bussiere JL, Chellman GJ, Ominsky MS, Pyrah IT (2014) Infant cynomolgus monkeys exposed to denosumab in utero exhibit an osteoclast-poor osteopetrotic-like skeletal phenotype at birth and in the early postnatal period. Bone 64:314–325. https://doi.org/10.1016/j.bone.2014.04.002

    Article  CAS  PubMed  Google Scholar 

  • Brown HR, Castellino S, Groseclose MR, Elangbam CS, Mellon-Kusibab K, Yoon LW, Gates LD, Krull DL, Cariello NF, Arrington-Brown L, Tillman T, Fowler S, Shah V, Bailey D, Miller RT (2016) Drug-induced liver fibrosis: testing Nevirapine in a viral-like liver setting using histopathology, MALDI IMS, and gene expression. Toxicol Pathol 44(1):112–131. https://doi.org/10.1177/0192623315617033

    Article  CAS  PubMed  Google Scholar 

  • Bussiere JL, Leach MW, Price KD, Mounho BJ, Lightfoot-Dunn R (2011) Survey results on the use of the tissue cross-reactivity immunohistochemistry assay. Regul Toxicol Pharmacol 59(3):493–502

    Article  CAS  PubMed  Google Scholar 

  • Carson FL (1997) Histotechnology- a self-instructional text. ASCP Press, Chicago

    Google Scholar 

  • Carter CL, Jones JW, Barrow K, Kieta K, Taylor-Howell C, Kearney S, Smith CP, Gibbs A, Farese AM, MacVittie TJ, Kane MA (2015) A MALDI-MSI approach to the characterization of radiation-induced lung injury and medical countermeasure development. Health Phys 109(5):466–478. https://doi.org/10.1097/HP.0000000000000353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carter CL, Parker GA, Hankey KG, Farese AM, MacVittie TJ, Kane MA (2018) MALDI-MSI spatially maps N-glycan alterations to histologically distinct pulmonary pathologies following lethal-doses of irradiation. Scientific Reports in prep

    Google Scholar 

  • Crabbs TA, Miller RA, Malarkey DE (2013) Poster: centriacinar lung lesions in control rats associated with oral gavage administration. Paper presented at the 2013 ESTP, Ghent, Belgium

    Google Scholar 

  • Cullen JM, Falls JG, Brown HR, Yoon LW, Cariello NF, Faiola B, Kimbrough CL, Jordan HL, Miller RT (2010) Time course gene expression using laser capture microscopy-extracted bile ducts, but not hepatic parenchyma, reveals acute alpha-naphthylisothiocyanate toxicity. Toxicol Pathol 38(5):715–729

    Article  CAS  PubMed  Google Scholar 

  • de Groot DM, Hartgring S, van de Horst L, Moerkens M, Otto M, Bos-Kuijpers MH, Kaufmann WS, Lammers JH, O’Callaghan JP, Waalkens-Berendsen ID, Pakkenberg B, Gundersen HG (2005) 2D and 3D assessment of neuropathology in rat brain after prenatal exposure to methylazoxymethanol, a model for developmental neurotoxicty. Reprod Toxicol 20(3):417–432

    Article  PubMed  CAS  Google Scholar 

  • Doyle N, Varela A, Haile S, Guldberg R, Kostenuik PJ, Ominsky MS, Smith SY, Hattersley G (2017) Abaloparatide, a novel PTH receptor agonist, increased bone mass and strength in ovariectomized cynomolgus monkeys by increasing bone formation without increasing bone resorption. Osteoporos Int. https://doi.org/10.1007/s00198-017-4323-6

  • Dunnick JK, Merrick BA, Brix A, Morgan DL, Gerrish K, Wang Y, Flake G, Foley J, Shockley KR (2016) Molecular changes in the nasal cavity after N, N-dimethyl-p-toluidine exposure. Toxicol Pathol 44(6):835–847. https://doi.org/10.1177/0192623316637708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Emmert-Buck MR, Bonner RF, Smith PD, Chuaqui RF, Zhuang Z, Goldstein SR, Weiss RA, Liotta LA (1996) Laser capture microdissection. Science 274(5289):998–1001

    Article  CAS  PubMed  Google Scholar 

  • Espina V, Wulfkuhle JD, Calvert VS, VanMeter A, Zhou W, Coukos G, Geho DH, Petricoin EF 3rd, Liotta LA (2006) Laser-capture microdissection. Nat Protoc 1(2):586–603

    Article  CAS  PubMed  Google Scholar 

  • Greijdanus-van der Putten SW, van Esch E, Kamerman J, Ballering LA, van den Dobbelsteen DJ, TdR EP (2005) Drug-induced protoporphyria in beagle dogs. Toxicol Pathol 33(6):720–725

    Article  CAS  PubMed  Google Scholar 

  • Gundersen HJ, Jensen EB (1987) The efficiency of systematic sampling in stereology and its prediction. J Microsc 147(Pt 3):229–263

    Article  CAS  PubMed  Google Scholar 

  • Haley PJ (2012) Small molecule immunomodulatory drugs: challenges and approaches for balancing efficacy with toxicity. Toxicol Pathol 40(2):261–266

    Article  CAS  PubMed  Google Scholar 

  • Hall WC, Price-Schiavi SA, Wicks J, Rojko JL (2008) Tissue cross-reactivity studies for monoclonal antibodies: predictive value and use for selection of relevant animal species for toxicity testing. In: Cavagnaro JA (ed) Preclinical safety evaluation of biopharmaceuticals: a science-based approach to facilitating clinical trials. Wiley, Hoboken, pp 207–240

    Chapter  Google Scholar 

  • Hanig J, Paule MG, Ramu J, Schmued L, Konak T, Chigurupati S, Slikker W Jr, Sarkar S, Liachenko S (2014) The use of MRI to assist the section selections for classical pathology assessment of neurotoxicity. Regul Toxicol Pharmacol 70(3):641–647. https://doi.org/10.1016/j.yrtph.2014.09.010

    Article  CAS  PubMed  Google Scholar 

  • Hillmann G, Hillman B, Donath K (1991) Enzyme, lectin and immunohistochemistry of plastic embedded undecalcified bone and other hard tissues for light microscopic investigations. Biotech Histochem 66(4):185–193

    Article  CAS  PubMed  Google Scholar 

  • Hockings PD, Roberts T, Campbell SP, Reid DG, Greenhill RW, Polley SR, Nelson P, Bertram TA, Kramer K (2002) Longitudinal magnetic resonance imaging quantitation of rat liver regeneration after partial hepatectomy. Toxicol Pathol 30(5):606–610

    Article  PubMed  Google Scholar 

  • Holland (2001) A survey of discriminant methods used in toxicological histopathology. Toxicol Pathol 29(2):269–273

    Google Scholar 

  • Holland T, Holland C (2011) Analysis of unbiased histopathology data from rodent toxicity studies (or, are these groups different enough to ascribe it to treatment?). Toxicol Pathol 39(4):569–575

    Article  PubMed  Google Scholar 

  • Hunt JA, Callaghan JT (2008) Polymer-hydroxyapatite composite versus polymer interference screws in anterior cruciate ligament reconstruction in a large animal model. Knee Surg Sports Traumatol Arthrosc 16(7):655–660. https://doi.org/10.1007/s00167-008-0528-8

    Article  PubMed  Google Scholar 

  • Hutto DL (2010) Opportunistic infections in non-human primates exposed to immunomodulatory biotherapeutics: considerations and case examples. J Immunotoxicol 7(2):120–127. https://doi.org/10.3109/15476910903258252

    Article  CAS  PubMed  Google Scholar 

  • IPCS (2004) International programme on chemical safety (IPCS) harmonization project: risk assessment terminology. Part 1: IPCS/OECD key generic terms used in chemical hazard/risk assessment. Part 2: IPCS glossary of key exposure assessment terminology. World Health Organization

    Google Scholar 

  • Irwin RD, Boorman GA, Cunningham ML, Heinloth AN, Malarkey DE, Paules RS (2004) Application of toxicogenomics to toxicology: basic concepts in the analysis of microarray data. Toxicol Pathol 32(Suppl 1):72–83

    Article  CAS  PubMed  Google Scholar 

  • Johnson AG, Badea A, Jiang Y (2011) Quantitative neuromorphometry using magnetic resonance histology. Toxicol Pathol 39(1):85–91

    Article  PubMed  Google Scholar 

  • Kerlin R, Bolon B, Burkhardt J, Francke S, Greaves P, Meador V, Popp J (2016) Scientific and Regulatory Policy Committee: recommended (“Best”) practices for determining, communicating, and using adverse effect data from nonclinical studies. Toxicol Pathol 44(2):147–162. https://doi.org/10.1177/0192623315623265

    Article  PubMed  Google Scholar 

  • Knudsen L, Ochs M (2011) Microscopy-based quantitative analysis of lung structure: application in diagnosis. Expert Opin Med Diag 5(4):319–331

    Article  Google Scholar 

  • Latendresse JR, Warbrittion AR, Jonassen H, Creasy DM (2002) Fixation of testes and eyes using a modified Davidson’s fluid: comparison with Bouin’s fluid and conventional Davidson’s fluid. Toxicol Pathol 30(4):524–533

    Article  PubMed  Google Scholar 

  • Leach MW, Halpern WG, Johnson CW, Rojko JL, Maclachlan TK, Chan CM, Galbreath EJ, Ndifor AM, Blanset DL, Polack E, Cavagnaro JA (2010) Use of tissue cross-reactivity studies in the development of antibody-based biopharmaceuticals: history, experience, methodology, and future directions. Toxicol Pathol 38(7):1138–1166

    Article  PubMed  Google Scholar 

  • Lenz B, Brink A, Siam M, De Paepe A, Bassett S, Eichinger-Chapelon A, Maliver P, Neff R, Niederhauser U, Steinhuber B, Zurbach R, Singer T, Funk C, Schuler F, Albassam M, Schadt S (2018) Application of imaging techniques to cases of drug-induced crystal nephropathy in preclinical studies. Toxicol Sci 163(2):409–419. https://doi.org/10.1093/toxsci/kfx044

    Article  CAS  PubMed  Google Scholar 

  • Leonovich SA (2010) The lung mite Pneumonyssus semicola Banks (Halarachidae) in lungs of the rhesus monkey Macaca mulatta. Acarina 18:89–90

    Google Scholar 

  • Luebke RW, Holsapple MP, Ladics GS, Luster MI, Selgrade M, Smialowicz RJ, Woolhiser MR, Germolec DR (2006) Immunotoxicogenomics: the potential of genomics technology in the immunotoxicity risk assessment process. Toxicol Sci 94(1):22–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maronpot RR, Nyska A, Troth SP, Gabrielson K, Sysa-Shah P, Kalchenko V, Kuznetsov Y, Harmelin A, Schiffenbauer YS, Bonnel D, Stauber J, Ramot Y (2017) Regulatory forum opinion piece∗: imaging applications in toxicologic pathology-recommendations for use in regulated nonclinical toxicity studies. Toxicol Pathol 45(4):444–471. https://doi.org/10.1177/0192623317710014

    Article  PubMed  Google Scholar 

  • Mascini NE, Eijkel GB, ter Brugge P, Jonkers J, Wesseling J, Heeren RM (2015) The use of mass spectrometry imaging to predict treatment response of patient-derived xenograft models of triple-negative breast cancer. J Proteome Res 14(2):1069–1075. https://doi.org/10.1021/pr501067z

    Article  CAS  PubMed  Google Scholar 

  • McLeod F, Marzo A, Podpolny M, Galli S, Salinas P (2017) Evaluation of synapse density in Hippocampal Rodent brain slices. (128):e56153. https://doi.org/10.3791/56153

  • Morgan KT, Ni H, Brown HR, Yoon L, Qualls CW Jr, Crosby LM, Reynolds R, Gaskill B, Anderson SP, Kepler TB, Brainard T, Liv N, Easton M, Merrill C, Creech D, Sprenger D, Conner G, Johnson PR, Fox T, Sartor M, Richard E, Kuruvilla S, Casey W, Benavides G (2002) Application of cDNA microarray technology to in vitro toxicology and the selection of genes for a real-time RT-PCR-based screen for oxidative stress in Hep-G2 cells. Toxicol Pathol 30(4):435–451

    Article  CAS  PubMed  Google Scholar 

  • Ominsky MS, Boyd SK, Varela A, Jolette J, Felx M, Doyle N, Mellal N, Smith SY, Locher K, Buntich S, Pyrah I, Boyce RW (2017) Romosozumab improves bone mass and strength while maintaining bone quality in ovariectomized cynomolgus monkeys. J Bone Miner Res 32(4):788–801. https://doi.org/10.1002/jbmr.3036

    Article  CAS  PubMed  Google Scholar 

  • Parker GA (2016) Pathology evaluation for detection of immunomodulation. In: Parker GA (ed) Immunopathology in toxicology and drug development, vol 1. Humana Press (Springer Nature), Cham, pp 371–432

    Google Scholar 

  • Parker GA, Snyder PW (2017) Pathology evaluation for detection of immunomodulation. In: Parker GA (ed) Immunopathology in toxicology and drug development, Molecular and integrative toxicology, vol 1, 1st edn. Springer International Publishing AG/Human Press, Cham, pp 371–442

    Chapter  Google Scholar 

  • Parker GA, Peng B, He M, Gould-Fogerite S, Chou CC, Raveche ES (2000) In vivo and in vitro antiproliferative effects of antisense interleukin 10 oligonucleotides. Methods Enzymol 314:411–429

    Article  CAS  PubMed  Google Scholar 

  • Picut CA, Swanson CL, Scully KL, Roseman VC, Parker RF, Remick AK (2008) Ovarian follicle counts using proliferating cell nuclear antigen (PCNA) and semi-automated image analysis in rats. Toxicol Pathol 36(5):674–679

    Article  PubMed  Google Scholar 

  • Pinheiro FA, Mourao CF, Diniz VS, Silva PC, Meirelles L, Santos Junior E, Schanaider A (2014) In-vivo bone response to titanium screw implants anodized in sodium sulfate. Acta Cir Bras 29(6):376–382

    Article  PubMed  Google Scholar 

  • Powers TW, Neely BA, Shao Y, Tang H, Troyer DA, Mehta AS, Haab BB, Drake RR (2014) MALDI imaging mass spectrometry profiling of N-glycans in formalin-fixed paraffin embedded clinical tissue blocks and tissue microarrays. PLoS One 9(9):e106255. https://doi.org/10.1371/journal.pone.0106255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramot Y, Schiffenbauer YS, Maronpot R, Nyska A (2017) Compact magnetic resonance imaging systems-novel cost-effective tools for preclinical drug safety and efficacy evaluation. Toxicol Sci 157(1):3–7. https://doi.org/10.1093/toxsci/kfx024

    Article  CAS  PubMed  Google Scholar 

  • Schafer KA, Eighmy J, Fikes JD, Halpern WG, Hukkanen RR, Long GG, Meseck EK, Patrick DJ, Thibodeau MS, Wood CE, Francke S (2018) Use of severity grades to characterize histopathologic changes. Toxicol Pathol 46(3):256–265. https://doi.org/10.1177/0192623318761348

    Article  CAS  PubMed  Google Scholar 

  • Schmued LC, Hopkins KJ (2000) Fluoro-Jade: novel fluorochromes for detecting toxicant-induced neuronal degeneration. Toxicol Pathol 28(1):91–99

    Article  CAS  PubMed  Google Scholar 

  • Schoeb TR, McConnell EE (2011a) Mycoplasma pulmonis and lymphoma in a methanol bioassay. Vet Pathol 48(4):903–905. https://doi.org/10.1177/0300985811404713

    Article  CAS  PubMed  Google Scholar 

  • Schoeb TR, McConnell EE (2011b) Commentary: further comments on mycoplasma pulmonis and lymphoma in bioassays of rats. Vet Pathol 48(2):420–426. https://doi.org/10.1177/0300985810377183

    Article  CAS  PubMed  Google Scholar 

  • Schoeb TR, McConnell EE, Juliana MM, Davis JK, Davidson MK, Lindsey JR (2009) Mycoplasma pulmonis and lymphoma in bioassays in rats. Vet Pathol 46(5):952–959. https://doi.org/10.1354/vp.08-VP-0240-S-COM

    Article  CAS  PubMed  Google Scholar 

  • Seaton M (2014) The study pathologist’s role in GLP studies: a regulator’s perspective. Toxicol Pathol 42(1):285. https://doi.org/10.1177/0192623313506878

    Article  PubMed  Google Scholar 

  • Shaltiel-Karyo R, Tsarfati Y, Rubinski A, Zawoznik E, Weinstock I, Nemas M, Schiffenbauer YS, Ramot Y, Nyska A, Yacoby-Zeevi O (2017) Magnetic resonance imaging as a noninvasive method for longitudinal monitoring of infusion site reactions following administration of a novel apomorphine formulation. Toxicol Pathol 45(4):472–480. https://doi.org/10.1177/0192623317706111

    Article  CAS  PubMed  Google Scholar 

  • Sheehan DC, Hrapchak BB (1980) Theory and practice of histotechnology. Battelle Press, Columbus

    Google Scholar 

  • Siegel S, Castellan HJ (1988) Nonparametric statistics for the behavioural sciences. McGraw-Hill, New York

    Google Scholar 

  • Sommers SC (1967) Systematized nomenclature of pathology. Pathol Microbiol (Basel) 30(5):826–827

    CAS  Google Scholar 

  • Sprent P, Smeeton NC (2007) Applied nonparametric statistical methods, 4th edn. Chapeman & Hall/CRC, Boca Raton

    Google Scholar 

  • Thompson SW (1966) Selected histochemical and histopathological methods. Charles C Thomas Publisher, Springfield

    Google Scholar 

  • van Gorder MA, Della Pelle P, Henson JW, Sachs DH, Cosimi AB, Colvin RB (1999) Cynomolgus polyoma virus infection: a new member of the polyoma virus family causes interstitial nephritis, ureteritis, and enteritis in immunosuppressed cynomolgus monkeys. Am J Pathol 154(4):1273–1284

    Article  PubMed  PubMed Central  Google Scholar 

  • Varela A, Chouinard L, Lesage E, Guldberg R, Smith SY, Kostenuik PJ, Hattersley G (2017) One year of abaloparatide, a selective peptide activator of the PTH1 receptor, increased bone mass and strength in ovariectomized rats. Bone 95:143–150. https://doi.org/10.1016/j.bone.2016.11.027

    Article  CAS  PubMed  Google Scholar 

  • Wu Y, Wu EX (2009) MR study of postnatal development of myocardial structure and left ventricular function. J Magn Reson Imaging 30(1):47–53

    Article  CAS  PubMed  Google Scholar 

  • Young B, Lowe JS, Stevens A, Heath JW (2006) Wheater’s functional histology-a text and colour atlas. Churchill Livingston (Elsevier), Philadelphia

    Google Scholar 

  • Zucker RM (2006) Quality assessment of confocal microscopy slide based systems: performance. Cytometry A 69(7):659–676. https://doi.org/10.1002/cyto.a.20314

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Global Pathology, Charles River Laboratories, Durham, NC, USA

    George A. Parker

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  1. George A. Parker
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Correspondence to George A. Parker .

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Editors and Affiliations

  1. North Carolina Laboratory, Experimental Pathology Laboratories, Inc., Durham, NC, USA

    Thomas J. Steinbach

  2. Charles River Laboratories, Inc., Mattawan, MI, USA

    Daniel J. Patrick

  3. MEC Regulatory and Toxicology Consulting, LLC, Moorpark, CA, USA

    Mary Ellen Cosenza

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Parker, G.A. (2019). Introduction to Toxicologic Pathology. In: Steinbach, T., Patrick, D., Cosenza, M. (eds) Toxicologic Pathology for Non-Pathologists. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9777-0_1

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