Critical assessment and integration of separate lines of evidence for risk assessment of chemical mixtures

Summary Humans are exposed to a large number of environmental chemicals: Some of these may be toxic, and many others have unknown or poorly characterized health effects. There is intense interest in determining the impact of exposure to environmental chemical mixtures on human health. As the study of mixtures continues to evolve in the field of environmental epidemiology, it is imperative that we understand the methodologic challenges of this research and the types of questions we can address using epidemiological data. In this article, we summarize some of the unique challenges in exposure assessment, statistical methods, and methodology that epidemiologists face in addressing chemical mixtures. We propose three broad questions that epidemiological studies can address: a) What are the potential health impacts of individual chemical agents? b) What is the interaction among agents? And c) what are the health effects of cumulative exposure to multiple agents? As the field of mixtures research grows, we can use these three questions as a basis for defining our research questions and for developing methods that will help us better understand the effect of chemical exposures on human disease and well-being. Show more

Pesticides almost always occur in mixtures with other ones. The toxicological effects of low-dose pesticide mixtures on the human health are largely unknown, although there are growing concerns about their safety. The combined toxicological effects of two or more components of a pesticide mixture can take one of three forms: independent, dose addition or interaction. Not all mixtures of pesticides with similar chemical structures produce additive effects; thus, if they act on multiple sites their mixtures may produce different toxic effects. The additive approach also fails when evaluating mixtures that involve a secondary chemical that changes the toxicokinetics of the pesticide as a result of its increased activation or decreased detoxification, which is followed by an enhanced or reduced toxicity, respectively. This review addresses a number of toxicological interactions of pesticide mixtures at a molecular level. Examples of such interactions include the postulated mechanisms for the potentiation of pyrethroid, carbaryl and triazine herbicides toxicity by organophosphates; how the toxicity of some organophosphates can be potentiated by other organophosphates or by previous exposure to organochlorines; the synergism between pyrethroid and carbamate compounds and the antagonism between triazine herbicides and prochloraz. Particular interactions are also addressed, such as those of pesticides acting as endocrine disruptors, the cumulative toxicity of organophosphates and organochlorines resulting in estrogenic effects and the promotion of organophosphate-induced delayed polyneuropathy. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved. Show more

Chemical regulation is challenged by the large number of chemicals requiring assessment for potential human health and environmental impacts. Current approaches are too resource intensive in terms of time, money and animal use to evaluate all chemicals under development or already on the market. The need for timely and robust decision making demands that regulatory toxicity testing becomes more cost-effective and efficient. One way to realize this goal is by being more strategic in directing testing resources; focusing on chemicals of highest concern, limiting testing to the most probable hazards, or targeting the most vulnerable species. Hypothesis driven Integrated Approaches to Testing and Assessment (IATA) have been proposed as practical solutions to such strategic testing. In parallel, the development of the Adverse Outcome Pathway (AOP) framework, which provides information on the causal links between a molecular initiating event (MIE), intermediate key events (KEs) and an adverse outcome (AO) of regulatory concern, offers the biological context to facilitate development of IATA for regulatory decision making. This manuscript summarizes discussions at the Workshop entitled "Advancing AOPs for Integrated Toxicology and Regulatory Applications" with particular focus on the role AOPs play in informing the development of IATA for different regulatory purposes. Copyright © 2014 Elsevier Inc. All rights reserved. Show more