C T De Rosa PhD H Hansen S Wilbur H R Pohl H A ElMasri M M Mumtaz

Environmental Exposures

We live in a chemical world, and exposure to xenobiotics is a fact of life. Humans are exposed daily to a variety of chemicals including but not limited to large categories of pesticides, pharmaceuticals, household products, and food additives. Chemical exposures can be intentional or unintentional, to a single chemical or to a mixture of chemicals. Exposures to environmental chemicals occur in populations living in inner cities near chemical manufacturing plants (1, 2) hazardous waste sites, and in the near field runoffs from fields and fertilizers (3). An overturned cargo train or transportation truck can spill chemicals in a pristine environment and become a source of pollution, contamination, and exposure, and eventually lead to an emergency response event. Exposures to environmental chemicals can affect humans, animals, and plants. Thus people of various interests and backgrounds are concerned about environmental exposures. Everyone carries a body burden of chemicals that range from primary elements and radioactive materials to synthetic, persistent chemicals such as dioxins, polychlorinated biphenyls (PCBs), and certain chlorinated 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.

Following a chemical exposure, the body exhibits a spectrum of biologic responses (Fig. 6.1) (1). For many chemicals, low-level human exposures do not produce observable health effects. Physiologically, the body adjusts to the presence of chemicals at this level through adaptive mechanisms. As chemical exposure increases, effects such as enzyme induction and certain biochemical and subcellular changes of uncertain significance may result. The body may have compensatory mechanisms at this level of chemical exposure (3). However, as chemical exposures continue to increase, observable adverse effects may ensue as the body exhausts its adaptive and compensatory mechanisms. Such adverse effects could lead to biochemical, pathophysiologic, histopathologic changes resulting in organ dysfunction. Exposure to higher levels of pollutants could lead to morbidity and mortality. Exposures from multiple sources or pathways may lower the threshold for adverse health effects along this continuum. Considering that humans generally lack homogeneity in biochemical characteristics, some groups within the population will be more susceptible to chemical exposures than others.

\ Adverse health

Mof&idity \ effects

Pathophysiologic changes

Philologie changes of uncertain significance

Pollutant burdens

"-Proportion of population affected-

Figure 6.1. Spectrum of biological response to environmental pollutant exposure.

Thus it is important that exposure to environmental chemicals be viewed in the context of overall chemical exposures. Concurrent exposures to chemicals such as welding fumes, indoor air pollutants, tobacco smoke, alcohol, and prescription and nonprescription drugs complicate the health risk assessment of low-level, involuntary, environmental exposure such as may occur at hazardous waste sites. Voluntary exposures to some chemicals frequently entail exposures to relatively high chemical concentrations and are usually well defined and quantifiable, whereas involuntary exposures from waste sites may be at low concentrations and difficult to characterize and quantify. Individual control over exposure varies across personal, occupational, and environmental chemical exposure pathways (Fig. 6.2). Personal exposures such as firsthand tobacco smoke or alcohol are voluntary. Occupational exposure is voluntary, but the individual generally has less control over these exposures. On the other hand, individuals usually have few options for controlling environmental exposures under ordinary circumstances. In most cases, other than relocation, there are no clear options for individual control over hazardous waste exposures. Often an individual may not even be aware of the site, the exposure pathways, or the nature of the exposure. In terms of concentrations, for general populations, personal exposures are usually at higher levels than hazardous waste exposures. Such combined exposures may produce obvious adverse health effects or compromise physiologic defenses that are necessary for maintaining homeostasis.

Figure 6.2. Human exposures to chemicals in the environment.

The potential for combined chemical exposures to compromise physiologic 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 (3). In such populations, pollutant burdens can initiate pathophysiologic changes at lower levels in comparison to the general population. For example, human infants and children differ from adults in size, immaturity of biochemical and physiologic functions in major body systems, and body composition in terms of proportions of water, fat, protein, mineral mass, and chemical constituents (4, 5). During the first 2 months of life, rapid development occurs in the brain (cell migration, neuron myelination, and creation of neuron synapses), lungs (developing alveoli), and bones (rapid growth). Development of the brain and lungs continues until age 12, at which time gonad maturation, ova and sperm maturations, and breast development occur (6). Depending on the chemical, the stage of growth and development may be a critical factor in determining toxicity (7). Finally, the contribution of hazardous waste to exposures of populations living near hazardous waste sites may constitute a significant contribution to overall body burdens when concurrent with occupational and personal exposures.

Historically, health concerns from exposure to single chemicals drive criteria derivation procedures. Usually, the target chemical, or group of chemicals, is identified by a government agency, international organization, or an advisory body based on legislative mandate, evidence or potential for human risk, or community concerns. For each chemical, exposure and health effects data are reviewed, and a single route-specific index of "acceptable" exposure is derived for the chemical. This approach is taken by several organizations such as the American Conference of Governmental Industrial Hygienists (ACGIH), the Agency for Toxic Substances and Disease Registry (ATSDR), the National Institute for Occupational Safety and Health (NIOSH), the U.S. Environmental Protection Agency (EPA), and the World Health Organization (WHO) (Table 6.1). However, most exposures are not to single chemicals, but to complex mixtures of chemicals that can affect public health through multiple routes 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 organizations and agencies to consider multiple chemical exposures, sequentially or simultaneously, while setting the criteria to protect public health from potential health effects of chemicals. Thus one has to consider comprehensive risk to populations that are exposed not only to a specific mixture but also to additional environmental agents and naturally occurring compounds that may enhance, inhibit, or contribute to the health risks posed by that mixture. In very few cases, the available information on a mixture and its components is reviewed and a criteria for the mixture are derived. The purpose of this chapter is to highlight 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 to promote the use of innovative techniques to advance joint toxicity assessment methods.

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