Comparative In Vitro Immunotoxicology of Organochlorine Mixtures: Validation for Use in Risk AssessmentEPA Grant Number: R829361
Title: Comparative In Vitro Immunotoxicology of Organochlorine Mixtures: Validation for Use in Risk Assessment
Investigators: DeGuise, Sylvain
Institution: University of Connecticut
EPA Project Officer: Louie, Nica
Project Period: October 1, 2001 through September 30, 2004 (Extended to September 30, 2005)
Project Amount: $666,649
RFA: Complex Chemical Mixtures (2000) RFA Text | Recipients Lists
Research Category: Hazardous Waste/Remediation , Land and Waste Management , Safer Chemicals
Marine mammals, like humans, are often at the top of the aquatic food chain, and accumulate multiple environmental contaminants such as organohalogens that are now ubiquitous in the aquatic ecosystem. Contaminant-related immunosuppression has long been suspected to explain disease susceptibility. Ample evidence that organohalogens have detrimental effects on the immune system of man and animals has been collected over the past three decades. Not surprisingly, PCB-induced immunosuppression results in a higher sensitivity of experimental animals to a wide variety of infectious agents such as bacteria, protozoa and viruses. Nevertheless, the immunotoxicity of mixtures of toxic compounds has rarely been evaluated. While some authors showed non-additive antagonistic interactions of PCB congeners in commercial mixtures, others suggested additive or synergistic effect. Our preliminary results demonstrated effects in belugas associated with mixtures that were different than those causing effects in mice. It is troubling that the immunotoxicity of some mixtures of chemicals in a mammal, the beluga, could not be detected using mice, the classic model in immunotoxicology. The effects of mixtures are particularly important to understand since they represent the "real life" exposure to environmental contaminants. The present project proposes to study the immunotoxic potential of simple mixtures of organochlorines (OCs) at relatively low concentrations on the immune functions of humans and different species of marine mammals, including beluga whales, bottlenose dolphin and harbor seals.
The mixtures to be tested represent all the possible combinations using five individual compounds: PCB IUPAC #138, 153, 169 and 180, as well as 2,3,7,8-TCDD. These mixtures will be used in in vitro immunological assays where functions of exposed cells will be compared to those of unexposed control cells. The significance of in vitro exposure to determine immunotoxicity compared to traditional in vivo exposures will be validated in mice. We will also test anew rapid and economical method of assessing exposure to PCBs using antibodies.
The outcomes of the proposed project will be on several aspects of toxicology. The development and validation of in vitro assays, if reliable and relevant to in vivo exposures, will provide an attractive and economical alternative to the in vivo assays for regulatory purposes. It will also provide an opportunity for some studies in species (such as humans, marine mammals and endangered species) for which controlled in vivo exposures would be impractical for logistic, economic as well as ethical reasons. Another significant outcome will be some clarification of the interactions (agonistic/antagonistic properties) of individual compounds in immunotoxicity of mixtures of OCs. This will provide directions and help define research hypothesis for further mechanistic studies. The expected results should also shed some light on the difference of susceptibility of different species of marine mammals to the immunotoxic effects of mixtures of OCs. This will be a useful tool for wildlife conservation as well as population and habitat management. Finally, a better understanding of marine mammal immunotoxicology may provide a good model for predicting the risk associated with life-long exposure to low concentrations of environmental contaminants in complex mixtures, such as experienced by human beings.