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. 2003 Apr;111(4):579–583. doi: 10.1289/ehp.5860

Consensus workshop on methods to evaluate developmental immunotoxicity.

Michael I Luster 1, Jack H Dean 1, Dori R Germolec 1
PMCID: PMC1241448  PMID: 12676619

Abstract

A workshop cosponsored by the National Institute of Environmental Health Sciences and the National Institute for Occupational Safety and Health was convened in Washington, DC, on 17-18 October 2001 with the goal of developing a consensus document on the most appropriate experimental approaches and assays available to assess developmental immunotoxicity. The work group was composed of scientists from academia, the chemical and pharmaceutical industries, and federal agencies with expertise in developmental immunology, developmental toxicology, immunotoxicology, and risk evaluation. This consensus document presents an overview of the major summations made by the work group. A summary of early work in the field is provided, which includes potential immunotoxic agents, followed by brief discussions of our current understanding of developmental immunology. This report concludes with the work group's consensus of the most appropriate experimental design and tests to screen for potential developmental immunotoxic agents in experimental models, including potential limitations and data gaps.

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Selected References

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  1. Barnett J. B., Barfield L., Walls R., Joyner R., Owens R., Soderberg L. S. The effect of in utero exposure to hexachlorobenzene on the developing immune response of BALB/c mice. Toxicol Lett. 1987 Dec;39(2-3):263–274. doi: 10.1016/0378-4274(87)90242-6. [DOI] [PubMed] [Google Scholar]
  2. Barnett J. B., Blaylock B. L., Gandy J., Menna J. H., Denton R., Soderberg L. S. Long-term alteration of adult bone marrow colony formation by prenatal chlordane exposure. Fundam Appl Toxicol. 1990 May;14(4):688–695. doi: 10.1016/0272-0590(90)90294-t. [DOI] [PubMed] [Google Scholar]
  3. Barnett J. B., Holcomb D., Menna J. H., Soderberg L. S. The effect of prenatal chlordane exposure on specific anti-influenza cell-mediated immunity. Toxicol Lett. 1985 Jun;25(3):229–238. doi: 10.1016/0378-4274(85)90202-4. [DOI] [PubMed] [Google Scholar]
  4. Blaylock B. L., Holladay S. D., Comment C. E., Heindel J. J., Luster M. I. Exposure to tetrachlorodibenzo-p-dioxin (TCDD) alters fetal thymocyte maturation. Toxicol Appl Pharmacol. 1992 Feb;112(2):207–213. doi: 10.1016/0041-008x(92)90189-y. [DOI] [PubMed] [Google Scholar]
  5. Bunn T. L., Parsons P. J., Kao E., Dietert R. R. Exposure to lead during critical windows of embryonic development: differential immunotoxic outcome based on stage of exposure and gender. Toxicol Sci. 2001 Nov;64(1):57–66. doi: 10.1093/toxsci/64.1.57. [DOI] [PubMed] [Google Scholar]
  6. Chapin R. E., Harris M. W., Davis B. J., Ward S. M., Wilson R. E., Mauney M. A., Lockhart A. C., Smialowicz R. J., Moser V. C., Burka L. T. The effects of perinatal/juvenile methoxychlor exposure on adult rat nervous, immune, and reproductive system function. Fundam Appl Toxicol. 1997 Nov;40(1):138–157. doi: 10.1006/faat.1997.2381. [DOI] [PubMed] [Google Scholar]
  7. Chen S., Golemboski K. A., Sanders F. S., Dietert R. R. Persistent effect of in utero meso-2,3-dimercaptosuccinic acid (DMSA) on immune function and lead-induced immunotoxicity. Toxicology. 1999 Jan 1;132(1):67–79. doi: 10.1016/s0300-483x(98)00139-5. [DOI] [PubMed] [Google Scholar]
  8. Dewailly E., Ayotte P., Bruneau S., Laliberté C., Muir D. C., Norstrom R. J. Inuit exposure to organochlorines through the aquatic food chain in arctic québec. Environ Health Perspect. 1993 Dec;101(7):618–620. doi: 10.1289/ehp.93101618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dietert R. R., Etzel R. A., Chen D., Halonen M., Holladay S. D., Jarabek A. M., Landreth K., Peden D. B., Pinkerton K., Smialowicz R. J. Workshop to identify critical windows of exposure for children's health: immune and respiratory systems work group summary. Environ Health Perspect. 2000 Jun;108 (Suppl 3):483–490. doi: 10.1289/ehp.00108s3483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dudley A. C., Peden-Adams M. M., EuDaly J., Pollenz R. S., Keil D. E. An aryl hydrocarbon receptor independent mechanism of JP-8 jet fuel immunotoxicity in Ah-responsive and Ah-nonresponsive mice. Toxicol Sci. 2001 Feb;59(2):251–259. doi: 10.1093/toxsci/59.2.251. [DOI] [PubMed] [Google Scholar]
  11. Ezine S., Papiernik M. Impairment of antibody response and of suppressor cell ontogenesis by early injection of hydrocortisone. Immunology. 1981 Jul;43(3):535–540. [PMC free article] [PubMed] [Google Scholar]
  12. Fadel S., Sarzotti M. Cellular immune responses in neonates. Int Rev Immunol. 2000;19(2-3):173–193. doi: 10.3109/08830180009088504. [DOI] [PubMed] [Google Scholar]
  13. Faith R. E., Luster M. I., Kimmel C. A. Effect of chronic developmental lead exposure on cell-mediated immune functions. Clin Exp Immunol. 1979 Mar;35(3):413–420. [PMC free article] [PubMed] [Google Scholar]
  14. Faith R. E., Moore J. A. Impairment of thymus-dependent immune functions by exposure of the developing immune system to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). J Toxicol Environ Health. 1977 Oct;3(3):451–464. doi: 10.1080/15287397709529578. [DOI] [PubMed] [Google Scholar]
  15. Figliomeni M. L., Turkall R. M. Developmental immunotoxicity of cocaine and ethanol in postnatal Lewis rats. Immunopharmacology. 1997 Apr;36(1):41–48. doi: 10.1016/s0162-3109(96)00153-1. [DOI] [PubMed] [Google Scholar]
  16. Fine J. S., Gasiewicz T. A., Silverstone A. E. Lymphocyte stem cell alterations following perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Mol Pharmacol. 1989 Jan;35(1):18–25. [PubMed] [Google Scholar]
  17. Garman R. H., Fix A. S., Jortner B. S., Jensen K. F., Hardisty J. F., Claudio L., Ferenc S. Methods to identify and characterize developmental neurotoxicity for human health risk assessment. II: neuropathology. Environ Health Perspect. 2001 Mar;109 (Suppl 1):93–100. doi: 10.1289/ehp.01109s193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gehrs B. C., Riddle M. M., Williams W. C., Smialowicz R. J. Alterations in the developing immune system of the F344 rat after perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin: II. Effects on the pup and the adult. Toxicology. 1997 Oct 19;122(3):229–240. doi: 10.1016/s0300-483x(97)00099-1. [DOI] [PubMed] [Google Scholar]
  19. Gehrs B. C., Smialowicz R. J. Persistent suppression of delayed-type hypersensitivity in adult F344 rats after perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology. 1999 May 3;134(1):79–88. doi: 10.1016/s0300-483x(99)00024-4. [DOI] [PubMed] [Google Scholar]
  20. Hardin J. A., Hinoshita F., Sherr D. H. Mechanisms by which benzo[a]pyrene, an environmental carcinogen, suppresses B cell lymphopoiesis. Toxicol Appl Pharmacol. 1992 Dec;117(2):155–164. doi: 10.1016/0041-008x(92)90232-h. [DOI] [PubMed] [Google Scholar]
  21. Holladay S. D., Lindstrom P., Blaylock B. L., Comment C. E., Germolec D. R., Heindell J. J., Luster M. I. Perinatal thymocyte antigen expression and postnatal immune development altered by gestational exposure to tetrachlorodibenzo-p-dioxin (TCDD). Teratology. 1991 Oct;44(4):385–393. doi: 10.1002/tera.1420440405. [DOI] [PubMed] [Google Scholar]
  22. Holladay S. D., Luster M. I. Alterations in fetal thymic and liver hematopoietic cells as indicators of exposure to developmental immunotoxicants. Environ Health Perspect. 1996 Aug;104 (Suppl 4):809–813. doi: 10.1289/ehp.96104s4809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Holladay S. D., Smialowicz R. J. Development of the murine and human immune system: differential effects of immunotoxicants depend on time of exposure. Environ Health Perspect. 2000 Jun;108 (Suppl 3):463–473. doi: 10.1289/ehp.00108s3463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Holsapple M. P. Developmental immunotoxicology and risk assessment: a workshop summary. Hum Exp Toxicol. 2002 Sep-Oct;21(9-10):473–478. doi: 10.1191/0960327102ht284oa. [DOI] [PubMed] [Google Scholar]
  25. Immunotoxicology Technical Committee, International Life Sciences Institute and Environmental Sciences Institute Application of flow cytometry to immunotoxicity testing: summary of a workshop. Toxicology. 2001 May 28;163(1):39–48. doi: 10.1016/s0300-483x(01)00364-x. [DOI] [PubMed] [Google Scholar]
  26. Kamath A. B., Nagarkatti P. S., Nagarkatti M. Characterization of phenotypic alterations induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin on thymocytes in vivo and its effect on apoptosis. Toxicol Appl Pharmacol. 1998 May;150(1):117–124. doi: 10.1006/taap.1998.8390. [DOI] [PubMed] [Google Scholar]
  27. Landreth K. S. Critical windows in development of the rodent immune system. Hum Exp Toxicol. 2002 Sep-Oct;21(9-10):493–498. doi: 10.1191/0960327102ht287oa. [DOI] [PubMed] [Google Scholar]
  28. Lee J. E., Chen S., Golemboski K. A., Parsons P. J., Dietert R. R. Developmental windows of differential lead-induced immunotoxicity in chickens. Toxicology. 2001 Jan 2;156(2-3):161–170. doi: 10.1016/s0300-483x(00)00350-4. [DOI] [PubMed] [Google Scholar]
  29. Levine T. E., Butcher R. E. Workshop on the qualitative and quantitative comparability of human and animal developmental neurotoxicity, Work Group IV report: triggers for developmental neurotoxicity testing. Neurotoxicol Teratol. 1990 May-Jun;12(3):281–284. doi: 10.1016/0892-0362(90)90100-q. [DOI] [PubMed] [Google Scholar]
  30. Luster M. I., Boorman G. A., Dean J. H., Harris M. W., Luebke R. W., Padarathsingh M. L., Moore J. A. Examination of bone marrow, immunologic parameters and host susceptibility following pre- and postnatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Int J Immunopharmacol. 1980;2(4):301–310. doi: 10.1016/0192-0561(80)90030-2. [DOI] [PubMed] [Google Scholar]
  31. Luster M. I., Faith R. E., Kimmel C. A. Depression of humoral immunity in rats following chronic developmental lead exposure. J Environ Pathol Toxicol. 1978 Mar-Apr;1(4):397–402. [PubMed] [Google Scholar]
  32. Luster M. I., Faith R. E., McLachlan J. A., Clark G. C. Effect of in utero exposure to diethylstilbestrol on the immune response in mice. Toxicol Appl Pharmacol. 1979 Feb;47(2):279–285. doi: 10.1016/0041-008x(79)90322-3. [DOI] [PubMed] [Google Scholar]
  33. Luster M. I., Munson A. E., Thomas P. T., Holsapple M. P., Fenters J. D., White K. L., Jr, Lauer L. D., Germolec D. R., Rosenthal G. J., Dean J. H. Development of a testing battery to assess chemical-induced immunotoxicity: National Toxicology Program's guidelines for immunotoxicity evaluation in mice. Fundam Appl Toxicol. 1988 Jan;10(1):2–19. doi: 10.1016/0272-0590(88)90247-3. [DOI] [PubMed] [Google Scholar]
  34. Luster M. I., Portier C., Pait D. G., Rosenthal G. J., Germolec D. R., Corsini E., Blaylock B. L., Pollock P., Kouchi Y., Craig W. Risk assessment in immunotoxicology. II. Relationships between immune and host resistance tests. Fundam Appl Toxicol. 1993 Jul;21(1):71–82. doi: 10.1006/faat.1993.1074. [DOI] [PubMed] [Google Scholar]
  35. Luster M. I., Portier C., Pait D. G., White K. L., Jr, Gennings C., Munson A. E., Rosenthal G. J. Risk assessment in immunotoxicology. I. Sensitivity and predictability of immune tests. Fundam Appl Toxicol. 1992 Feb;18(2):200–210. doi: 10.1016/0272-0590(92)90047-l. [DOI] [PubMed] [Google Scholar]
  36. Marshall-Clarke S., Reen D., Tasker L., Hassan J. Neonatal immunity: how well has it grown up? Immunol Today. 2000 Jan;21(1):35–41. doi: 10.1016/s0167-5699(99)01548-0. [DOI] [PubMed] [Google Scholar]
  37. Miller T. E., Golemboski K. A., Ha R. S., Bunn T., Sanders F. S., Dietert R. R. Developmental exposure to lead causes persistent immunotoxicity in Fischer 344 rats. Toxicol Sci. 1998 Apr;42(2):129–135. doi: 10.1006/toxs.1998.2424. [DOI] [PubMed] [Google Scholar]
  38. Parent-Massin D. Relevance of clonogenic assays in hematotoxicology. Cell Biol Toxicol. 2001;17(2):87–94. doi: 10.1023/a:1010906104558. [DOI] [PubMed] [Google Scholar]
  39. Ramos Gerardo, Nghiem Dat X., Walterscheid Jeffrey P., Ullrich Stephen E. Dermal application of jet fuel suppresses secondary immune reactions. Toxicol Appl Pharmacol. 2002 Apr 15;180(2):136–144. doi: 10.1006/taap.2002.9380. [DOI] [PubMed] [Google Scholar]
  40. Ridge J. P., Di Rosa F., Matzinger P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature. 1998 Jun 4;393(6684):474–478. doi: 10.1038/30989. [DOI] [PubMed] [Google Scholar]
  41. Schwetz B. A., Tyl R. W. Consensus workshop on the evaluation of maternal and developmental toxicity work group III report: low dose extrapolation and other considerations for risk assessment--models and applications. Teratog Carcinog Mutagen. 1987;7(3):321–327. doi: 10.1002/tcm.1770070313. [DOI] [PubMed] [Google Scholar]
  42. Silverstone A. E., Frazier D. E., Jr, Gasiewicz T. A. Alternate immune system targets for TCDD: lymphocyte stem cells and extrathymic T-cell development. Exp Clin Immunogenet. 1994;11(2-3):94–101. doi: 10.1159/000424198. [DOI] [PubMed] [Google Scholar]
  43. Smialowicz R. J., Riddle M. M., Rogers R. R., Luebke R. W., Copeland C. B. Immunotoxicity of tributyltin oxide in rats exposed as adults or pre-weanlings. Toxicology. 1989 Jul 3;57(1):97–111. doi: 10.1016/0300-483x(89)90037-1. [DOI] [PubMed] [Google Scholar]
  44. Smialowicz R. J., Riddle M. M., Rogers R. R., Rowe D. G., Luebke R. W., Fogelson L. D., Copeland C. B. Immunologic effects of perinatal exposure of rats to dioctyltin dichloride. J Toxicol Environ Health. 1988;25(4):403–422. doi: 10.1080/15287398809531220. [DOI] [PubMed] [Google Scholar]
  45. Smialowicz R. J., Williams W. C., Copeland C. B., Harris M. W., Overstreet D., Davis B. J., Chapin R. E. The effects of perinatal/juvenile heptachlor exposure on adult immune and reproductive system function in rats. Toxicol Sci. 2001 May;61(1):164–175. doi: 10.1093/toxsci/61.1.164. [DOI] [PubMed] [Google Scholar]
  46. Spyker-Cranmer J. M., Barnett J. B., Avery D. L., Cranmer M. F. Immunoteratology of chlordane: cell-mediated and humoral immune responses in adult mice exposed in utero. Toxicol Appl Pharmacol. 1982 Mar 15;62(3):402–408. doi: 10.1016/0041-008x(82)90141-7. [DOI] [PubMed] [Google Scholar]
  47. Stites D. P., Carr M. C., Fudenberg H. H. Ontogeny of cellular immunity in the human fetus: development of responses to phytohemagglutinin and to allogeneic cells. Cell Immunol. 1974 Mar 30;11(1-3):257–271. doi: 10.1016/0008-8749(74)90026-4. [DOI] [PubMed] [Google Scholar]
  48. Temple L., Kawabata T. T., Munson A. E., White K. L., Jr Comparison of ELISA and plaque-forming cell assays for measuring the humoral immune response to SRBC in rats and mice treated with benzo[a]pyrene or cyclophosphamide. Fundam Appl Toxicol. 1993 Nov;21(4):412–419. doi: 10.1006/faat.1993.1116. [DOI] [PubMed] [Google Scholar]
  49. Theus S. A., Tabor D. R., Soderberg L. S., Barnett J. B. Macrophage tumoricidal mechanisms are selectively altered by prenatal chlordane exposure. Agents Actions. 1992 Sep;37(1-2):140–146. doi: 10.1007/BF01987903. [DOI] [PubMed] [Google Scholar]
  50. Urso P., Gengozian N. Depressed humoral immunity and increased tumor incidence in mice following in utero exposure to benzo[alpha]pyrene. J Toxicol Environ Health. 1980 May;6(3):569–576. doi: 10.1080/15287398009529874. [DOI] [PubMed] [Google Scholar]
  51. Vos J. G., Moore J. A. Suppression of cellular immunity in rats and mice by maternal treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Int Arch Allergy Appl Immunol. 1974;47(5):777–794. doi: 10.1159/000231268. [DOI] [PubMed] [Google Scholar]
  52. Vos J. G., van Logten M. J., Kreeftenberg J. G., Steerenberg P. A., Kruizinga W. Effect of hexachlorobenzene on the immune system of rats following combined pre- and postnatal exposure. Drug Chem Toxicol. 1979;2(1-2):61–76. doi: 10.3109/01480547908993182. [DOI] [PubMed] [Google Scholar]
  53. Ways S. C., Mortola J. F., Zvaifler N. J., Weiss R. J., Yen S. S. Alterations in immune responsiveness in women exposed to diethylstilbestrol in utero. Fertil Steril. 1987 Aug;48(2):193–197. doi: 10.1016/s0015-0282(16)59341-8. [DOI] [PubMed] [Google Scholar]
  54. Weisglas-Kuperus N., Sas T. C., Koopman-Esseboom C., van der Zwan C. W., De Ridder M. A., Beishuizen A., Hooijkaas H., Sauer P. J. Immunologic effects of background prenatal and postnatal exposure to dioxins and polychlorinated biphenyls in Dutch infants. Pediatr Res. 1995 Sep;38(3):404–410. doi: 10.1203/00006450-199509000-00022. [DOI] [PubMed] [Google Scholar]
  55. Weissman I. L., Anderson D. J., Gage F. Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annu Rev Cell Dev Biol. 2001;17:387–403. doi: 10.1146/annurev.cellbio.17.1.387. [DOI] [PubMed] [Google Scholar]
  56. del Arco I., Muñoz R., Rodríguez De Fonseca F., Escudero L., Martín-Calderón J. L., Navarro M., Villanúa M. A. Maternal exposure to the synthetic cannabinoid HU-210: effects on the endocrine and immune systems of the adult male offspring. Neuroimmunomodulation. 2000;7(1):16–26. doi: 10.1159/000026416. [DOI] [PubMed] [Google Scholar]

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