Introduction to Toxicologic Pathology

  • George A. ParkerEmail author


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.

Key words

Pathology Histopathology Toxicologic pathology Toxicology Safety assessment 


  1. 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. Scholar
  2. Bloom W, Fawcett DW, Raviola E (1994) A textbook of histology. Chapman & Hall, New YorkGoogle Scholar
  3. 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. Scholar
  4. 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):947–953PubMedGoogle Scholar
  5. 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):211–221PubMedGoogle Scholar
  6. Boyce JT, Boyce RW, Gundersen HJ (2010a) Choice of morphometric methods and consequences in the regulatory environment. Toxicol Pathol 38(7):1128–1133PubMedGoogle Scholar
  7. 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):1011–1025PubMedGoogle Scholar
  8. 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. Scholar
  9. 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. Scholar
  10. 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):493–502PubMedGoogle Scholar
  11. Carson FL (1997) Histotechnology- a self-instructional text. ASCP Press, ChicagoGoogle Scholar
  12. 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. Scholar
  13. 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 prepGoogle Scholar
  14. 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, BelgiumGoogle Scholar
  15. 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):715–729PubMedGoogle Scholar
  16. 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):417–432PubMedGoogle Scholar
  17. 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.
  18. 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. Scholar
  19. Emmert-Buck MR, Bonner RF, Smith PD, Chuaqui RF, Zhuang Z, Goldstein SR, Weiss RA, Liotta LA (1996) Laser capture microdissection. Science 274(5289):998–1001PubMedGoogle Scholar
  20. 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):586–603PubMedGoogle Scholar
  21. 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):720–725PubMedGoogle Scholar
  22. Gundersen HJ, Jensen EB (1987) The efficiency of systematic sampling in stereology and its prediction. J Microsc 147(Pt 3):229–263PubMedGoogle Scholar
  23. Haley PJ (2012) Small molecule immunomodulatory drugs: challenges and approaches for balancing efficacy with toxicity. Toxicol Pathol 40(2):261–266PubMedGoogle Scholar
  24. 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 207–240Google Scholar
  25. 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. Scholar
  26. 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):185–193PubMedGoogle Scholar
  27. 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):606–610PubMedGoogle Scholar
  28. Holland (2001) A survey of discriminant methods used in toxicological histopathology. Toxicol Pathol 29(2):269–273Google Scholar
  29. 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):569–575PubMedGoogle Scholar
  30. 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. Scholar
  31. Hutto DL (2010) Opportunistic infections in non-human primates exposed to immunomodulatory biotherapeutics: considerations and case examples. J Immunotoxicol 7(2):120–127. Scholar
  32. 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 OrganizationGoogle Scholar
  33. 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):72–83PubMedGoogle Scholar
  34. Johnson AG, Badea A, Jiang Y (2011) Quantitative neuromorphometry using magnetic resonance histology. Toxicol Pathol 39(1):85–91PubMedGoogle Scholar
  35. 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. Scholar
  36. Knudsen L, Ochs M (2011) Microscopy-based quantitative analysis of lung structure: application in diagnosis. Expert Opin Med Diag 5(4):319–331Google Scholar
  37. 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):524–533PubMedGoogle Scholar
  38. 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):1138–1166PubMedGoogle Scholar
  39. 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. Scholar
  40. Leonovich SA (2010) The lung mite Pneumonyssus semicola Banks (Halarachidae) in lungs of the rhesus monkey Macaca mulatta. Acarina 18:89–90Google Scholar
  41. 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):22–27PubMedPubMedCentralGoogle Scholar
  42. 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. Scholar
  43. 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. Scholar
  44. McLeod F, Marzo A, Podpolny M, Galli S, Salinas P (2017) Evaluation of synapse density in Hippocampal Rodent brain slices. (128):e56153.
  45. 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):435–451PubMedGoogle Scholar
  46. 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. Scholar
  47. 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 371–432Google Scholar
  48. 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 371–442Google Scholar
  49. 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 314:411–429PubMedGoogle Scholar
  50. 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):674–679PubMedGoogle Scholar
  51. 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):376–382PubMedGoogle Scholar
  52. 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. Scholar
  53. 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. Scholar
  54. 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. Scholar
  55. Schmued LC, Hopkins KJ (2000) Fluoro-Jade: novel fluorochromes for detecting toxicant-induced neuronal degeneration. Toxicol Pathol 28(1):91–99PubMedGoogle Scholar
  56. Schoeb TR, McConnell EE (2011a) Mycoplasma pulmonis and lymphoma in a methanol bioassay. Vet Pathol 48(4):903–905. Scholar
  57. Schoeb TR, McConnell EE (2011b) Commentary: further comments on mycoplasma pulmonis and lymphoma in bioassays of rats. Vet Pathol 48(2):420–426. Scholar
  58. 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. Scholar
  59. Seaton M (2014) The study pathologist’s role in GLP studies: a regulator’s perspective. Toxicol Pathol 42(1):285. Scholar
  60. 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. Scholar
  61. Sheehan DC, Hrapchak BB (1980) Theory and practice of histotechnology. Battelle Press, ColumbusGoogle Scholar
  62. Siegel S, Castellan HJ (1988) Nonparametric statistics for the behavioural sciences. McGraw-Hill, New YorkGoogle Scholar
  63. Sommers SC (1967) Systematized nomenclature of pathology. Pathol Microbiol (Basel) 30(5):826–827Google Scholar
  64. Sprent P, Smeeton NC (2007) Applied nonparametric statistical methods, 4th edn. Chapeman & Hall/CRC, Boca RatonGoogle Scholar
  65. Thompson SW (1966) Selected histochemical and histopathological methods. Charles C Thomas Publisher, SpringfieldGoogle Scholar
  66. 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):1273–1284PubMedPubMedCentralGoogle Scholar
  67. 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. Scholar
  68. Wu Y, Wu EX (2009) MR study of postnatal development of myocardial structure and left ventricular function. J Magn Reson Imaging 30(1):47–53PubMedGoogle Scholar
  69. Young B, Lowe JS, Stevens A, Heath JW (2006) Wheater’s functional histology-a text and colour atlas. Churchill Livingston (Elsevier), PhiladelphiaGoogle Scholar
  70. Zucker RM (2006) Quality assessment of confocal microscopy slide based systems: performance. Cytometry A 69(7):659–676. Scholar

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Authors and Affiliations

  1. 1.Global Pathology, Charles River LaboratoriesDurhamUSA

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