Thomas Hartung, University of Konstanz, Konstanz, Germany
Published online: September 2016
The immune system can be the target of many chemicals, with potentially adverse effects on the host's health. Over the past
two decades, little has changed in the practice of immunotoxicity testing for regulatory purposes. Current guidelines still
rely on animal tests, which include some immune endpoints in repeated dose tests and call for dedicated tests when alerts
indicate a problem. At the same time, a wealth of in vitro approaches has been developed, but little has been adopted for routine testing. The extent to which immunotoxicity of chemicals
represents a health problem at low levels of exposure is not clear: it appears that responses of healthy individuals to immunological
challenges differ widely and most immunomodulators have little adverse effects, except when coinciding with an infectious
or malignant challenge or when exposure early in life is expected, where the odds of progressing into infection and autoimmune
diseases as well as cancer can be changed. The enormous overcapacity of immune defense, the presence of compensatory mechanisms
and their fast restoration contribute to limiting health threats for the individual, although on a population base minor immunomodulations
might also result in increased morbidities. In vitro alternative approaches might offer an opportunity to screen for problematic substances and prioritising them for in vivo testing.
- Chemicals and drugs have been associated with various types of immune modulation including allergy/sensitisation, autoimmunity,
inflammation and immunosuppression, mainly in high‐dose animal experiments.
- The majority of substances has never been tested as to immune effects.
- It is not clear to which extent immuntoxicity of environmental chemicals produces public health effects, especially for immunosuppression.
- The guidance how to test is limited, mainly based on assessment of immune organs in repeated dose (chronic) animal tests.
- A number of in vitro tests have become available but only few have been pre‐validated so far.
- Immunotoxicity and inflammation should be part of future integrated testing strategies.
Keywords: immune system; chemical effects; xenobiotics; toxicity testing; alternative methods; hypersensitivity; allergy; autoimmunity; risk assessment; toxicology; immunodeficiency
European Commission (2006) Consolidated Version of Directive 67/548/EEC. Annex V Methods for the Detection of Physio‐chemical Properties, Toxicity and Ecotoxicity. Part B: Methods for the Determination of Toxicity and Other Health Effects (210 pp). http://ec.europa.eu/environment/dansub/pdfs/annex5b_en.pdf; Note: Part B of Annex V of Directive 67/548/EEC, as referenced above, was included in the EC (2003) proposal for the REACH regulation. It is not part of the final REACH Regulation (EC) No. 1907/2006 of 18 December 2006.
Hartung T and Corsini E (2013) Immunotoxicology: challenges in the 21st century and in vitro opportunities. ALTEX 30: 411–426.
OECD (2005) Guidance Document on the Validation and International Acceptance of New or Updated Test Methods for Hazard Assessment. OECD Series on Testing and Assessment, Guidance Document 34. Paris, France: Environment Directorate, Organisation for Economic Cooperation and Development. ENV/JM/MONO(2005)14.
OECD (2013) Guidance Document on Developing and Assessing Adverse Outcome Pathways. ENV/JM/MONO(2013)6.
Basketter DA, Clewell H, Kimber I, et al. (2012) A roadmap for the development of alternative (non‐animal) methods for systemic toxicity testing ‐ t4 report. ALTEX 29: 3–91.
Carfi M, Gennari A, Malerba I, et al. (2007) In vitro tests to evaluate immunotoxicity: a preliminary study. Toxicology 229: 11–22.
Corsini E (2006) Human immunotoxicology: consequences and mechanisms. Toxicology Letters 164: S313.
Corsini E and Roggen EL (2009) Immunotoxicology: opportunities for non‐animal test development. Alternatives to Laboratory Animals 37: 387–397.
Dean JH, House RV and Luster MI (2007) Immunotoxicology: effects of and response to drugs and chemicals. In: Hayes AW (ed.) Principles and Methods of Toxicology, 5th edn, pp. 1755–1796. Philadelphia: Taylor & Francis.
Descotes J (2006) Methods of evaluating immunotoxicity. Expert Opinion on Drug Metabolism & Toxicology 2: 249–259.
Dietert RR (ed.) (2010) Immunotoxicity Testing. Totowa, NJ: Humana Press.
Gennari A, Ban M, Braun A, et al. (2005) The use of in vitro systems for evaluating immunotoxicity: the report and recommendations of an ECVAM workshop. Journal of Immunotoxicology 2: 61–83.
House RV, Luebke R and Kimber I (2006) Immunotoxicology and Immunopharmacology. Boca Raton: CRC Press.
Luster MI and Gerberick GF (2010) Immunotoxicology testing: past and future. Methods in Molecular Biology 598: 3–13.