Standard Article


  1. C. T. De Rosa Ph.D.

Published Online: 17 AUG 2012

DOI: 10.1002/0471435139.tox006.pub2

Patty's Toxicology

Patty's Toxicology

How to Cite

De Rosa, C. T. 2012. Interactions. Patty's Toxicology. 6:419–448.

Publication History

  1. Published Online: 17 AUG 2012


All populations are exposed daily to a variety of chemicals including, but not limited to, large categories of pesticides, pharmaceuticals, household products, and food additives. These exposures may often be intentional or unintentional, to a single chemical or to a mixture of chemicals, either sequentially or simultaneously. Exposures occur in populations living near chemical manufacturing and hazardous waste sites and in the near field runoffs from fields and fertilizers. Transport spills from overturned cargo trains or transportation trucks also constitute potential sources of pollution, contamination, and exposure and eventually lead to an emergency response event. The impact of environmental chemical contamination is evident in part, body burden of chemicals that range from primary elements and radioactive materials to synthetic, persistent organopollutants such as dioxins, polychlorinated biphenyls (PCBs), and pesticides. The major issue is not whether we are being exposed to mixtures of chemicals, but whether these exposure levels exceed the body's ability to detoxify, adapt, or otherwise compensate before the on set of clinical disease.

Following chemical exposure, the body may exhibit a spectrum of biological responses. For many chemicals, low-level human exposures do not produce readily observable health effects. Physiologically, the body adjusts to the presence of chemicals at this level through a range of adaptive mechanisms. As chemical exposures increase in duration, frequency, and levels, effects such as enzyme induction and subcellular and biochemical changes of uncertain significance may result. However, as chemical exposures continue to increase, observable adverse effects may ensue as the body exhausts its adaptive and compensatory mechanisms. Such adverse effects may lead to biochemical, pathophysiological, and histopathological changes, resulting in organ dysfunction and ultimately morbidity and mortality. Exposures from multiple sources or pathways may lower the threshold for adverse health effects along this continuum. Some groups within the population will be more susceptible to chemical exposures than others due to genetic polymorphisms that vary in frequency in different populations.

For these reasons, environmental chemical exposures must be viewed in the context of all exposures. The potential for combined accidental chemical exposures to compromise physiological systems may be greater in susceptible populations that include children, elderly persons, women of childbearing age, fetuses, persons with certain genetic disorders, and persons with preexisting infirmities.

Historically, health concerns associated with exposure to single chemicals were the basis for health guidance values (HGV's) and associated regulatory approaches. However, most exposures are not to single chemicals, but to complex mixtures of chemicals that can affect health status through multiple pathways of exposure. The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA, or Superfund) of 1980, the Clean Air Act of 1990, and the Food Quality and Protection Act of 1996 all mandate that multiple chemical exposures, sequentially or simultaneously, be assessed for potential health effects of chemicals. This chapter highlights issues relevant to the joint toxicity assessment of chemical mixtures through the use of representative published studies, to present the alternative experimental testing approaches for mixtures, and highlights the potential role of innovative techniques to strengthen the technical premises of methods used to assess the potential for joint toxicity action of environmental contaminants.


  • environmental exposure;
  • mixtures exposure pathways;
  • interactions;
  • joint toxic action;
  • toxic equivalency factors;
  • weight-of-evidence methods;
  • risk assessment