Human Toxicology of Chemical Mixtures

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Evaluation of synergism or antagonism for the combined action of antiviral agents. Evaluation of experimental combined toxicity by use of dose-frequency curves: Can J Physiol Pharmacol. Symptoms of car painters with long-term exposure to a mixture of organic solvents. Scand J Work Environ Health. Experimental designs and risk assessment in combination toxicology: Exposure to mixtures of chemical substances: Confusion of concepts in mixture toxicology.

Experimental designs, statistics and interpretation. Chemical mixtures from a public health perspective: Exposure of humans to complex chemical mixtures: Statistical designs in combination toxicology: Use of factorial designs in combination toxicity studies. Strategies for toxicological evaluation of mixtures. Zero interaction response surfaces for combined-action assessment. Inhalation experiments with mixtures of hydrocarbons. Experimental design, statistics and interpretation of kinetics and possible interactions.

Sensory irritation to mixtures of formaldehyde, acrolein, and acetaldehyde in rats. Toxicity of formaldehyde and acrolein mixtures: Subacute toxicity of a mixture of nine chemicals in rats: Statistically designed experiments to screen chemical mixtures for possible interactions. Toxicology of chemical mixtures: EPA must develop air quality criteria for each chemical, detailing the scientific rationale for regulation. Under the CAA the U.

EPA a ; Worobec EPA ; Worobec Under the CWA the U. EPA is directed to develop water quality criteria outlining permissible pollutant loadings for a particular water use and states are directed to set water quality standards that include limitations on individual chemicals [for a summary see U. EPA b and Worobec ]. EPA recommends that water quality, water chemistry, and cumulative impacts of individual chemicals and chemical mixtures be addressed through methods that may include single-chemical, whole-effluent toxicity testing WET and bioassays U.

WET addresses complex chemical mixtures U. EPA , ; however, because they are designed primarily for the protection of aquatic health rather than human health, they will not be discussed further in this overview. It is unclear how often multiple chemical impacts are actually addressed. We rely upon both surface water protected by the CWA and groundwater for drinking.

Concerns about complex mixtures of disinfection by-products DBPs in drinking water, for example, have led to research on the reproductive and developmental toxicity of DBPs Simmons et al. EPA to track industrial chemicals and to more collectively consider all uses of a particular chemical or chemical mixture with a focus on human health and environmental impacts TSCA Note, however, that the language of TSCA seems to refer only to commercial or industrial mixtures rather than mixtures resulting from separate processes involving several different chemicals TSCA ; U.

Because some of the first risk assessment techniques addressing chemical mixtures were developed for worker protection OSHA , OSHA is included in this overview.

OSHA was designed in part to protect workers from exposure to harmful chemicals through establishment of standards and guidelines for individual chemicals. Before its enactment in , industry, industrial hygienists, and workers recognized the need for worker protection. The method was fairly straightforward: OSHA gave the Occupational Safety and Health Administration the authority to adopt existing occupational exposure limits as legally enforceable exposure limits.

Together, the chemical control laws reviewed above make up the bulk of laws that govern the production and use of chemicals in drugs, food, consumer products, and the workplace, and control the release of chemicals into the environment. In large part, these laws focus on individual chemicals, and it is likely that before and after their enactment, a great deal of energy and funding were directed toward further use and development of single-chemical testing.

The rationale for a single-chemical approach in situations where multiple chemicals exist is partly based on the premise that chemical interactions either do not occur or are not toxicologically important at very low concentrations e. Depending on the end point e. The potential for biologic effects below NOAEL, whether stimulatory or other, highlights the need, as discussed above, for research on potential interactions at these low concentrations.

It is within these laws that the issue of chemical mixtures is most explicitly addressed. The primary goal of RCRA is to protect humans and the environment from contaminants by empowering the U. EPA a , g. Notably, the guidance document for RCRA facility investigation allows for consideration of the additive health risk from multiple chemicals when assessing the site U. EPA b , h. To aid risk assessors in the evaluation of chemical mixtures, the U.

Human Toxicology of Chemical Mixtures

EPA developed guidance documents for the assessment of human health impacts from chemical mixtures U. EPA , EPA b , has also initiated a chemical mixtures program, which includes the development of a guidance document for chemical mixtures assessment and several interaction profiles for commonly occurring chemical mixtures discussed below in this overview ATSDR EPA is a compilation of several different approaches to mixtures.

Both this document and its predecessor include methodology cited by other agencies, including the Air Force Center for Environmental Excellence, which defers to U. Selected sections of the U. EPA document are reviewed below. As with any guidance document, its use is at the discretion of the risk assessor. For complex mixtures, particularly those that consist of commonly produced commercial or industrial mixtures, the preferred method is to use mixture-specific toxicity data.

This method is most appropriate for complex mixtures such as diesel fuels for which a great deal of toxicity data exist on the mixtures as a whole e. PCBs are another mixture that at times has been treated as a complex mixture, with toxicity tests on specific PCB mixtures e.

However, once released into the environment, depending on the mixture, previous use, route of release into the environment, and time in environment, the components of a mixture such as diesel fuel or PCBs may be altered i. As a result, the mixture for which toxicologic data exist may not be identical in composition to the mixture in the environment. Unfortunately, toxicity data on whole mixtures or similar mixtures are seldom available for chemical mixtures other than the original commercial or industrial mixture. According to the U. EPA, should any information reveal the potential for interaction i.

In the absence of evidence of chemical interaction, assumption of no interaction is the default approach, although, as discussed above, few data are available on chemical interactions, particularly at very low concentrations. Dose addition is suggested for chemicals that have similar toxicologic end points and toxicokinetics and for which either a lack of interaction is assumed or demonstrated through experimental data. In this case, similar toxicologic end points means chemicals that act by the same mechanism e. The dose addition methodology assumes that the potency of each chemical in the mixture can be calculated relative to each other or to one common chemical.

The RPF for a chemical is scaled according to its potency relative to an index chemical, a select chemical that is well characterized toxicologically and considered representative of the chemicals in the mixture. Chemicals that act through cholinesterase inhibition are suitable candidates for RPF methodology, and the U. RPFs for all like-acting chemicals are scaled relative to chlorophos by calculating the ratio of a common measure of potency, such as the dose concentration U. The contribution of each individual chemical in terms of chlorophos equivalent exposure is determined by multiplying the RPF by either a calculated or measured quantity of each chemical [e.

The predicted response is then quantitated using the sum of equivalent exposures and the dose—response curve for the index chemical. In this way, the RPF method provides a means for treating this kind of chemical mixture as a single chemical. The TEF is considered by the U.

TEFs have been developed for several organochlorines that act primarily via the aryl hydrocarbon receptor, using 2,3,7,8-tetrachlorodibenzo- p -dioxin TCDD as the reference chemical Van den Berg et al. The cumulative impact of the mixture is derived using the concentration of each chemical and the appropriate TEF U. With the HI, as with the RPF, there is an assumption that the impact of the chemicals is cumulative yet not interactive and involves adding up component concentrations.

In this case, chemicals for which reference doses RfDs or reference concentrations for inhalation are available and that have been identified as chemicals of concern at the site are scaled using a common end point such as the RfD. The RfD is based on the NOAEL derived through toxicity testing, including subchronic and chronic whole-animal studies for the most sensitive end point, or the critical effect U.

This use of the critical effect assumes protection against any other toxic effects that may occur from exposure to the chemical. This ratio produces a relative potency.

Toxicology

These scaled concentrations are then added together to develop the HI for the whole mixture. If the HI is equal to one, then the total exposure is interpreted as being equal to the mixture RfD U. Anything greater than one would represent a total concentration that is above the RfD, the interpretation of which would likely depend upon the situation and involve some judgment on the part of the risk assessor.

EPA b , although assessors are not required to do so. When using this approach, the U. EPA suggests using response addition for chemicals that act so differently—the presence of one chemical in no way affects the toxicity of another chemical [ U. EPA ; i. The primary application of response addition has been limited to the assessment of chemical carcinogens, although the U. Response addition is used because each chemical in the mixture has a different critical effect rather than a common critical end point.

EPA , could be used to estimate risk for each chemical and then summed to determine a cumulative risk. Because numerically adding risks will work only when there are low individual risks, this method would apply only to chemicals present in small concentrations. When applying additive methodology, if all chemicals in a mixture do not contribute to toxicity, or if an antagonistic interaction occurs, an assumption of additivity could produce an overestimate of risk.

Similarly, synergistic interactions might result in an underestimate. However, when first compiled, the database consisted primarily of binary studies and included only a small fraction of the potential chemical combinations that could exist at hazardous waste sites Hertzberg and MacDonell The authors of that study suggested that these differences might result from differences in the timing or sequence of chemical exposure, observations of different target organs, or different end points.

Addressing only these issues e. The interaction-based HI method is based on the HI but is designed to incorporate interaction data from binary testing to modify the HI. EPA , the method was developed explicitly to use binary interaction data and assumes that binary interactions reflect most of the possible interactions of the mixture. For example, a chemical combination of two chemicals A and B might affect the metabolic function of the liver and the heart, respectively. Chemical B is detoxified by the liver. If the liver is affected by chemical A, and its ability to detoxify chemical B is reduced, then combined exposure to these chemicals would result in enhanced toxicity, or a synergistic interaction.

The influence of a third chemical C would then be assessed according to its binary interactions, first with A and then with B. The three-way interaction of A, B, and C would not be addressed explicitly but would be assumed to be not as significant as the two-way interactions.

The weight of evidence is dependent upon data available within the binary mixtures database and requires some judgment by the risk assessor in determining the nature of the chemical interaction, such as direction of the interaction e. If available, the magnitude of interaction would be incorporated as well.

EPA conducted an evaluation of the application of dose addition for noncarcinogens and response addition for carcinogens, using the Comprehensive Environmental Response, Compensation, and Liability Information System database U. Mixtures assessments by the U. EPA and other agencies merit expanded analysis. This brief overview of chemical regulation, toxicology, and the U. EPA guidance document brings up several important considerations in mixtures assessment: As a result, the U.

EPA guidance is to some extent constrained by these data limitations.

Chemical Mixtures: Considering the Evolution of Toxicology and Chemical Assessment

These methods generally rely on default assumptions whose validity is unknown. Although the concept of chemical interaction is not new, a new focus on mixtures has arisen in all areas of toxicology and regulatory policy in the United States. The need for improved chemical and toxicologic data and methodology for chemical mixtures to which the public is exposed has resulted in several initiatives by U.

The ATSDR has also developed, through literature review, interaction profiles for nine commonly occurring mixtures e. The profiles, although often reliant on binary combinations, provide a detailed bibliography and literature review on selected mixtures and may at least highlight mixtures that depart from the assumption of additivity. Additionally, other agencies such as the NIEHS, National Toxicology Program, and National Institute for Occupational Safety and Health have also begun programs to characterize exposures, develop biomarkers, and evaluate environmentally relevant mixtures Bucher and Lucier Collaborative efforts should involve not just toxicologists and their traditional collaborators e.

Additionally, new research approaches could incorporate community knowledge; for example, health surveys conducted by community members in collaboration with public health professionals might be used in addition to oral histories collected by agencies such as the ATSDR or the Occupational Safety and Health Administration. Including a community perspective e. Toxicologists and others such as those working in genetics, molecular toxicology, or the newly developing field of toxicogenomics Feron et al.

Consideration of chemical mixtures adds yet another layer of complexity. Although one approach to reduce complexity may be to prioritize effects thought to be reliable predictors of health e. For example, although laboratory researchers had reported a range of endocrine or neuroendocrine toxicity in fish and wildlife for decades Colborn and Clement , many of these end points were not considered for human toxicity testing of industrial chemicals or standards development until the s.

EPA was directed to develop a screening program to identify the effects of chemicals on the endocrine system U. The Endocrine Disruptor Screening and Testing Advisory Committee was initiated to provide recommendations for the development of a screening program that would serve to provide information on endocrine-disrupting chemicals for regulatory application Ankley et al. An improved database on individual chemical toxicity developed using new techniques or end points e. These clusters, however have three common characteristics. First, they all followed exposures to chemical mixtures than contained at least one lipophilic fat soluble and one hydrophilic water soluble component.

Second, the specific combinations of lipophiles and hydrophiles act as individual entities and produce cancers not associated with exposure to any of the individual chemicals contained in the mixtures. Third, the cancers that follow these exposures can be in the form of single or multiple cancers per cluster. This research sheds new light on the causes of childhood leukemia outbreaks in Fallon, Nevada and Woburn, Massachusetts as well as on other previously unexplained cancer clusters.

Several breast cancer clusters that are being investigated also fit this model.

Zeliger is also the author of Human Toxicology of Chemical Mixtures.

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