Exposure Assessment

Exposure assessment is the process of measuring or estimating the intensity, frequency, and duration of human exposures to an agent currently present in the environment, or of estimating hypothetical exposures that might arise from the release of new chemicals into the environment.

Exposure assessments include environmental measurements (levels in air, water, soil, food, etc.) and physiological measurements (levels in blood, urine, and tissue samples), both of which provide essential information for wildlife, epidemiological, and experimental studies.

Exposure assessments can provide an accurate representation of the dose received by an individual. Although an individual may be exposed to a certain concentration of an agent, many factors will determine the effective concentration of the agent that organs, tissues and cells are actually exposed to. A chemical agent must persist in the environment long enough to interact with an organism (exposure). The biochemical properties of the agent (water solubility, sensitivity to heat, light) will determine the lifespan of an agent in the environment following its release. PCBs are stable chemicals that may persist in the environment for many years. The natural degradation of PCBs is dependent on the chlorine content of the chemical. The greater the chlorine content the less degradation will occur in soil but photodegradation will be enhanced from water surfaces and the atmosphere. The half-life of small, less chlorinated PCBs in the atmosphere is estimated to be 10-25 hours of direct noon sun while for more highly chlorinated PCBs the half-life is approximately 6 years.

Source of Exposure
Exposure to endocrine toxicants in the environment, both synthetic and naturally-occurring, can occur from a variety of sources. Humans are exposed to natural endocrine toxicants such as phytoestrogens through the consumption of plant products. Involuntary exposure to synthetic endocrine toxicants can occur through contaminated drinking water, contaminated air, food or contact with contaminated soil. Voluntary exposure to synthetic endocrine toxicants may occur through use of commercial products which contain endocrine toxicants including cleaners, pesticides, food additives, herbal supplements, cosmetics and medications.

PCBs, for example, are primarily present in the atmosphere in the vapour phase with a small portion in the particulate phase. The proportion of PCBs in the particulate phase varies inversely with ambient temperature and the vapour pressure of the PCB, such that a higher proportion of PCBs in the particulate phase is produced with lower ambient temperatures and vapour pressure. PCBs can be carried in the atmosphere, changing phases depending on temperature and vapour pressure, to contaminate surface water or soil.

Living organisms are an important source of endocrine toxicants. Persistent endocrine toxicants, such as PCBs or DDT, can contaminate plants and small organisms that are then consumed by larger animals. Progression up the food chain, with each animal consuming greater quantities of contaminated species on the lower levels of the food chain, magnifies the concentration of the contaminant consumed. This process is called 'biaccumulation' or 'biomagnification'. High levels of persistent endocrine toxicants (PCBs, DDT) have been found in carnivorous birds, seals, whales and polar bears. As water is a major source of endocrine toxicants, aquatic wildlife or animals that depend on these species for food, exhibit higher levels of contamination than land-dwelling wildlife. As these persistent chemicals are lipophilic (fat soluble), organisms with a high lipid content tend to have higher levels of contamination.

Routes of Exposure
There are three primary routes of exposure to chemical contaminants; dermal (skin-absorbed), respiratory (inhaled), and gastrointestinal (ingested). How chemicals enter the body is dependent on the properties of the chemical and the biology of the organism. Hydrophobic chemicals (not soluble in water) may be absorbed dermally such as PCBs and DDT. Chemicals that are volatile and exist as a gas may be inhaled. Fish may be exposed to chemicals through their gills during respiration.

For most vertebrates the primary route of exposure is gastroinstestinal. Herbivores (plant eating animals) are exposed to phytoestrogens through their consumption of plants. Carnivores are exposed to chemicals through their consumption of contaminated animals. Both of these are examples of bioaccumulation, as toxicants are magnified in the food-chain. The bacteria inhabiting the gastrointestinal tract can contribute to contaminant exposure. Certain contaminants may be broken down to form alternate congeners (chemical family member) which may be more or less biologically active. Other factors including the pH of the gastrointestinal tract and the time for digestion affect the chemical structure of toxicants, and thus, their biological activity.

An important route of dietary exposure is lactation. Endocrine toxicants and other chemicals have been shown to be secreted in breast milk for many species. These chemicals often retain their biological activity and thus, may be detrimental to the nursing offspring. Many factors affect the concentration of chemicals in lactated milk including maternal age, weight, number of births, duration of lactation and fat content of milk. As most toxicants are accumulated gradually through the diet, bioaccumulation of toxicants would be expected to increase with age. Maternal weight or rather, body fat, contributes to the concentration of chemicals in milk as persistent lipophilic chemicals are stored in fat deposits. Factors that reduce body burdens of accumulated contaminants are number of births and duration of lactation. Nursing first born children would be exposed to a higher concentration of chemicals from breast milk compared to subsequent children. Similarly, a longer period of lactation would increase exposure to the offspring while reducing the maternal body burden of the contaminant. Through lactational transfer some species can reduce their body burden of contaminants by as much as 60-80%. Species that produce milk with a high fat content are able to transfer more lipid-soluble toxicants to their offspring via nursing compared to species that produce milk with a lower fat content. Phytoestrogens are commonly found in both breast milk and bovine milk. A popular alternative to bovine milk is soy milk substitute, derived from soy. However, soy milk substitutes contain much greater amounts of phytoestrogens than animal milk. It is unknown whether exposure to phytoestrogens through consumption of soy milk substitute poses a risk to human health.

Once inside the body, contaminants travel to organs and tissues via the bloodstream. Blood sampling to measure the concentration of a particular contaminant is therefore an accepted method to assess exposure. Blood sampling is less invasive than other forms of sampling, and thus is often used for monitoring. The levels of contaminants in blood are often much less than tissue levels. Determination of the distribution of toxicants is essential to exposure assessment estimations. At any given time, toxicants are present bound to plasma proteins, unbound in blood, in adipose (fat) tissue and in tissues or organs. Depending on the methods used, blood sampling might only reveal the amount of a particular toxicant in an unbound form, thereby underestimating total exposure. Lipophilic chemicals travel through the bloodstream bound to carrier proteins or plasma proteins, similar to endogenous hormones. As many endocrine receptors are located intracellularly, chemicals must be free to pass from capillaries into cells to cause an effect. It is the unbound fraction of these chemicals that are considered biologically active. Proteins that bind hormones include steroid-hormone binding globulins (SHBGs) and non-specific proteins such as albumins. Different endocrine toxicants will have unique interactions with plasma proteins including the type of plasma protein and the kinetics of association (binding) and dissociation with the plasma protein. Thus, the concentration of plasma proteins in the bloodstream, the type of protein, the plasma flow rate and the binding kinetics between contaminants and their plasma proteins will affect the amount of biologically available toxicant.

Barriers to Exposure
The body has natural barriers to guard against chemical and biological invasion. These barriers can be physical (skin), biochemical (pH), enzymatic (enzymes) and chemical (hydrophobic cell membranes). Key internal barriers are present to protect the most sensitive organs from the action of drugs and chemicals. The brain is protected by the 'blood-brain barrier'. Specialized cells packed tightly together along with a glial sheath comprise the barrier. The capillaries are tightly joined preventing penetration by most compounds. To penetrate this barrier, toxicants must pass directly through the capillary wall which has no pores unlike capillaries in other organs. The barrier prevents transfer of hydrophilic (water soluble) drugs and compounds from the circulatory system to the brain. However, lipophilic toxicants can pass through the capillary wall and have been detected in brains of both humans and animals. The areas of the brain that control reproductive function lie outside the blood-brain barrier and are thus, not protected.

The developing fetus is highly sensitive to the effects of toxicant and chemical exposure. The placenta constitutes a barrier to prevent maternal-fetal transfer of some compounds. The placental barrier consists of a network of maternal blood vessels which are separated from fetal blood vessels by cell membranes. Thus, as with most cell membranes, lipophilic substances pass through the placental barrier easily while hydrophilic substances diffuse less readily. As many endocrine toxicants are lipophilic, the placenta does not prevent the transfer of toxicants between mother and fetus.

Timing of Exposure
Timing of exposure is critical to the understanding of dose-response relationships for endocrine toxicants. Numerous examples exist in the literature where age at exposure is a known risk factor. For example, endocrine disruption of the developing brain can permanently alter behavior, whereas similar exposures to a fully differentiated brain could be without effect. Generally, developing organ systems are vulnerable to chemical insult. These critical windows of exposure include fetal development, childhood, adolescence and other periods of sensitivity. Determination of the risks posed by a potential toxicant must consider the timing of exposure. Similarly, animal models should be selected on the basis of comparative physiology during these sensitive periods of development. Timing of exposure is a complex variable as there may be several years between toxicant exposure and a detectable effect or outcome. Many epidemiological studies attempt to ascertain fetal exposure to toxicants through the use of retrospective questionnaires completed by the mothers many years later, in many instances following development of an adverse effect in the offspring. The development of appropriate animal models could prove invaluable to further investigate the importance of exposure timing and extrapolation to humans.

Other steps in risk assessment consist of: hazard identification, dose-response assessment, and risk characterization.