Combination effects of pesticides on birth weight and metabolic programming in rat offspring

Risk assessment of pesticides is generally based on the no observed adverse effect levels (NOAELs) for single compounds. For mixtures of endocrine disrupting chemicals including pesticides, there is human and especially experimental evidence showing that substantial mixture effects on reproductive development can occur even though each of the individual chemicals is present at low, ineffective doses. These findings have major implications for the human risk assessment, as they imply that the current use of NOAELs for single chemicals may lead to an underestimation of the potential risk for humans exposed to mixtures of chemicals.
Decreased birth weight, which is an indicator of adverse intrauterine environment, is a common effect for many pesticides. Presently, there is no scientifically robust data available for evaluating potential mixture effects on this endpoint and for selecting the best model for predicting the mixture effects, i.e. dose-addition or independent action (DA or IA). Decreased birth weight is a developmental toxicity effect that is likely to be induced via many different and in most cases unknown mechanisms of action. Consequently, it is relevant to study combined effects of pesticides with dissimilar modes of action and evaluate the predictive value by applying both the IA and the DA model.
Low birth weight is in both humans and experimental animals a marker for a non-optimal prenatal development and is generally a predictor for increased risk for a long list of diseases later in life, including obesity and type 2 diabetes. The most widely accepted mechanisms thought to underlie these relationships are those of foetal programming and it is suggested that the foetus adapts physiologically in response to changes in the environment to prepare for postnatal life. Thus, it is considered very relevant to evaluate whether decreased birth weight is related to an altered metabolic programming during development.
The project has the following main objectives:
• Investigate whether a mixture of environmentally relevant pesticides, with dissimilar modes of action, will cause decreased birth weights at dose levels below NOAELs for the individual pesticides, in a developmental toxicity mixture study in rats.
• Based on existing data submitted for approval of the pesticides, evaluate whether the mixture effect is best predicted by the independent action or the dose-addition model.
• Investigate the influences of developmental pesticide exposure on metabolic programming of the offspring, using biomarkers for obesity and type 2 diabetes
• Give input for regulatory considerations on cumulative risk assessment of pesticides causing decreased birth weight, in order to take account of the potentially serious predictive value of this endpoint.