Health Effects of Exposures to Chemical Mixtures

Traditionally, toxicologists have addressed the effects of chemical mixtures as being additive, antagonistic, potentiated, or synergistic [1]. To these, sequential effects are also added here. 

Additive effects occur when two or more substances with the same toxicity (i.e., attack the same organ) are present together. The total or additive effect is the sum of the individual effects. Additive effects are observed when mixtures consist of species that are similar, that is, act identically on a target organ. Additive effects may be observed, for example, when a mixture of two compounds, each below the no-observed-exposme-level (NOEL), produces a predicted toxic effect when the sum of their concentrations is greater than the threshold level for toxic action. 

Examples of chemical mixtures that produce additive effects are  

n-Hexane and methyl- -butyl ketone (peripheral neuropathy) [2]. 

Antagonism occurs when two chemicals interfere with each other s effect. The result is a reduction in the effect predicted for the individual species. Antagonistic mixtures need not be structurally similar. One species may stimulate the metabolism of a second one or somehow interfere with its sorption. Antagonism can be considered the antithesis of synergism (discussed later). 

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Various approaches have been suggested in the scientific literature for use in the evaluation of the health risks from exposure to mixtures of chemicals. Most attention and effort has been devoted to procedures to assess cumulative effects of exposure to chemicals that act by a similar mechanism/mode of action (US-EPA 2000a), in which case the concept of dose addition applies. 

In addition to uncertainty in exposure, dose, and cancer estimations, the possibility of multiple simultaneous exposures to different chemicals needs to be considered. Risks from simultaneous exposure to more than one carcinogenic substance are typically estimated by assuming that the individual risks are additive. This process assumes that intakes of individual substances are relatively small, that there are no synergistic or antagonistic chemical interactions, and that all chemicals produce the same toxic effect (US EPA 1989). However, because health risks from exposures to chemical mixtures are generally based on a combination of upper-bound risks calculated for individual compounds, these risk assessments tend to be overly conservative (Gaylor and Chen 1996 Hwang and Chen 1999 Kodell and Chen 1994). 

As described in Chapter 1, the Navy has developed an approach for the management of mixtures of toxic gases in disabled submarines. That approach uses a cumulative exposure index (CEI), which assumes that the effects of exposure to mixtures of the irritant gases are additive but not synergistic. The subcommittee concludes that the use of the CEI approach is appropriate in protecting the health of the crew. That conclusion is consistent with the conclusions regarding the effects of exposure to mixtures of chemicals in other NRC... 

These cases led me to hypothesize that exposures to chemical mixtures could produce strange effects. A review of the literature revealed many examples of unexplained health effects on humans following exposures to mixtures. A study of these showed that in every unexplained instance the mixture contained at least one lipophilic (fat soluble) and one hydrophilic (water soluble) chemical. The literature showed that all body tissues have lipophilic barriers surrounding them. This suggested that absorption of lipophilic chemicals should occur more easily than for hydrophilic species. This too was confirmed by the literature and it was then hypothesized that lipophiles facilitate the absorption of admixed hydrophiles. 

The assessment of acute and chronic adverse effects induced by chemicals in both human and ecological (plants, animals, ecological chains, and ecosystems) targets is one of the most important scopes of environmental toxicology and sciences. In particular, the evaluation of the risk derived from the exposure to complex mixtures from environmental and diet sources is a challenging task which needs strategies, efforts, and time to reach the objectives of health protection. 

Given these possibilities, our exposure to complex mixtures of synthetic chemicals could be responsible for a portion of the background health effects measured in our society. 

Toxicologists have only just begun to study the influence of individual synthetic chemicals at low levels on human health. Unfortunately, toxicologists know virtually nothing about the toxic effects of chemical mixtures. Given these unknowns, our exposure to complex mixtures of synthetic chemicals could be responsible for a portion of the background health effects measured in our society. 

Environmental exposures are present through the human lifetime. However, they may vary considerably over time at the same location, for example, because of the local or global changes in emission and environmental pollution levels. Environmental exposures of humans consist of exposures outdoors and indoors as well as at workplaces these environments may significantly differ. The exposure media include air, water, and soil and dust. Historically, research on human exposures to chemicals and associated health effects has been conducted mostly on single chemicals. In addition, several studies have dealt with complex mixtures, such as diesel fuel and gasoline, by-products from coal combustion, and tobacco smoke. A common problem of complex mixtures is that the composition may vary from one exposure to another and, as a result, the associated toxicity may vary. For a better understanding... 

Component-Based Methods. Component-based approaches (Figure 5.5) are generally used to evaluate human health risks from exposure to a limited number of chemicals as a mixture. Key issues for component-based assessments include similarity in dose-response curves and similar vs. independent toxic modes of action (MOAs) among mixture components. A distinction can be made between 1) assessments using relatively simple additivity methods without the consideration of potential interaction effects, and 2) assessments that include data on toxicological interactions. Both types of assessments are discussed in more detail below. 

The potential for unusual health effects of chemical mixtures due to the interaction of chemicals or their metabolites (e.g., metabolites of trichloroethylene and benzene) in or with the biosystem constitutes a real issue in the public health arena. However, toxicity testing to predict effects on humans has traditionally studied one chemical at a time for various reasons convenient to handle, physiochemical properties readily defined, dosage could easily be controlled, biologic fate could easily be measured, and relevant data were often available from human occupational exposures. Chemicals are known to cause disease for example, arsenic and skin cancer, asbestos and lung cancer, lead and decrements of IQ, and hepatitis B predisposes to aflatoxin-induced liver cancer but the link between the extent of human exposure to even well-defined chemical mixtures and disease formation remains relatively unexplored, but of paramount importance to public health. 

The levels of all tested chemicals were either at low levels or not found. It should be noted that it is probable that other molecular species were also present, as irradiation is known to cleave molecules and produce aldehydes, ketones, and other species that are largely hydrophilic. The study concluded that the health effects noted were not the result of exposures to emissions from irradiated mail, despite the fact that the employees had other clinically evident symptoms, including nose bleed, itching skin, and skin rashes. It is opined here that the low level mixture of lipophiles and hydrophiles was indeed responsible for the neurotoxic and other effects reported and that the impacts on workers were inappropriately ignored. 

Verhaar et al. (1997), however, recently reported on progress in developing PBPK/PD models for use in assessing human health risks from exposure to JP-5, a Navy Jet petroleum fuel containing a complex mixture of hydrocarbons in the C9-C18 range. Verhaar et al. (1997) noted that their in-progress development of a PBPK/PD model for JP-5 is focused on the prediction of kinetics of JP-5 components in relevant tissues after acute inhalation exposure and the resultant toxicity (neurological effects linked to the dissolution of xenobiotic chemicals in the membrane of nerve cells). Verhaar et al. (1997) discussed how the development of PBPK/PD model(s) for complex mixtures involves ... 

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