Developmental immunotoxicity of chemicals in rodents and its possible regulatory impact.
Around 25% of the children in developed countries are affected with immune-based diseases. Juvenile onset diseases such as allergic, inflammatory and autoimmune diseases have shown increasing prevalences in the last decades. The role of chemical exposures in these phenomena is unclear. It is thought that the developmental immune system is more susceptible to toxicants than the mature situation. Developmental immunotoxicity (DIT) testing is nowadays not or minimally included in regulatory toxicology requirements. We reviewed whether developmental immune parameters in rodents would provide relatively sensitive endpoints of toxicity, whose inclusion in regulatory toxicity testing might improve hazard identification and risk assessment of chemicals. For each of the nine reviewed toxicants, the developing immune system was found to be at least as sensitive or more sensitive than the general (developmental) toxicity parameters. Functional immune (antigen-challenged) parameters appear more affected than structural (non-challenged) immune parameters. Especially, antibody responses to immune challenges with keyhole limpet hemocyanine or sheep red blood cells and delayed-type hypersensitivity responses appear to provide sensitive parameters of developmental immune toxicity. Comparison with current tolerable daily intakes (TDI) and their underlying overall no observed adverse effect levels showed that for some of the compounds reviewed, the TDI may need reconsideration based on developmental immune parameters. From these data, it can be concluded that the developing immune system is very sensitive to the disruption of toxicants independent of study design. Consideration of including functional DIT parameters in current hazard identification guidelines and wider application of relevant study protocols is warranted.
National Institute for Public Health and the Environment (RIVM), Center for Health Protection , Bilthoven , the Netherlands.
Ellen V S
EV
Hessel
Elisa C M
EC
Tonk
Peter M J
PM
Bos
Henk
H
van Loveren
Aldert H
AH
Piersma
D000818:Animals; D002648:Child; D015386:Hazardous Substances / Q000633:toxicity; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000453:epidemiology / Q000276:immunology; D007107:Immune System / Q000187:drug effects; D007154:Immune System Diseases / Q000139:chemically induced* / Q000453:epidemiology / Q000276:immunology; D019055:No-Observed-Adverse-Effect Level; D018570:Risk Assessment / Q000379:methods*; D012377:Rodentia; D012756:Sheep; D018675:Toxicity Tests / Q000379:methods*
D015386:Hazardous Substances
DEHP; DOTC; EOGRTS; Ethanol; MeHg; OECD 443; allergy; developmental immunotoxicity; immune system; juvenile; rat