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ToxSci Advance Access published online on August 24, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi299
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received June 30, 2005
Accepted August 21, 2005

Forum

Developmental Toxicology Evaluations - Issues with Including Neurotoxicology and Immunotoxicology Assessments in Reproductive Toxicology Studies

Gregory S. Ladics 1*, Robert E. Chapin 2, Kenneth L. Hastings 3, Michael P. Holsapple 4, Susan L. Makris 5, Larry P. Sheets 6, Michael R. Woolhiser 7, and Leigh Ann Burns-Naas 8

1 The DuPont Company., Haskell Laboratory, Newark, DE 19714
2 Worldwide Safety Sciences, Pfizer Global Research and Development, Groton, CT 06340
3 United States Food and Drug Administration, Center for Drug Evaluation Research, Office of New Drugs, Rockville, MD 20857
4 ILSI Health and Environmental Sciences Institute, Washington, DC 20005-5802
5 United States Environmental Protection Agency, National Center for Environmental Assessment, Washington, DC 20460-0001
6 Bayer CropScience LP, Stilwell, KS 66085-9104
7 The Dow Chemical Company, Toxicology & Environmental Research and Consulting, Midland, MI 48674
8 Worldwide Safety Sciences, Pfizer Global Research and Development, San Diego, CA 92064

* To whom correspondence should be addressed.
Gregory S. Ladics, E-mail: gregory.s.ladics{at}usa.dupont.com


  Abstract

Developmental and reproductive toxicology [DART] has routinely been a part of safety assessment. Attention is now focused on the effects of chemicals on the developing nervous and immune systems. This focus on developmental neurotoxicology (DNT) and developmental immunotoxicology (DIT) is based on the premise that children differ from adults in some aspects of their biology, and thus may also differ in their responses to chemicals. This session's objective was to discuss issues common to DNT and DIT as they relate to DART protocols, including high dose selection and maternal toxicity; adequacy of pup exposure during lactation; use of a different dosing paradigm for DART vs. DNT or DIT studies; whether DIT and DNT endpoints can be incorporated into a single DART study for hazard identification purposes. Consensus was achieved on all topics except the adequacy for risk assessment purposes of the use of a limited number of endpoints for DIT and DNT, with the DNT endpoints being the primary focus of disagreement. Panelists indicated that a combination study design for hazard identification was feasible, though flexibility to meet the scientific needs of the project was emphasized. The adequacy of existing triggers for additional developmental studies was also questioned. Panelists iterated the importance of understanding pup exposure during the various life stages and the use of toxicokinetic data in designing these studies. The group agreed to consider the HESI ACSA Life Stages Task Force recommendations as a next step to address some of the issues and challenges raised during this session.

Keywords: developmental immunotoxicology; DIT; developmental neurotoxicology; DNT; developmental and reproductive toxicology; DART; study design; combination study; hazard identification; panel discussion.
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