PRINCIPLES OF ENVIRONMENTAL TOXICOLOGY AND CONTAMINATION (PART II)

Table of Contents

1. Index
2. UNIT 5 - Transport and fate of contaminants in the environment
3. UNIT 6 - Principles of toxicokinetics and toxicodynamics
   1. Introduction
   2. Toxicokinetics
   3. Factors that affect toxicity: Species Differences
   4. Toxicokinetic and toxicodynamic models
4. UNIT 7 - Biotransformation
5. UNIT 8 - Toxicity Testing
6. Glossary of key terms associated with environmental toxicology

Factors that affect toxicity: Species Differences

Many factors (e.g.: anatomy and physiology, genetic variability, sex and hormonal status, environmental factor such as temperature, pH, UV, etc.) can influence the rates of absorption, metabolism and excretion, or even the distribution of the chemical within the body. Differences in these rates can impact chemical toxicity.

3.1 ANATOMY AND PHYSIOLOGY

The anatomy and physiology of an organism play key roles in defining the toxicity of a chemical to that organism. For example:

• Absorption through the skin is different across species. Some species have feathers or fur, which may protect against chemicals reaching the skin to be absorbed. For example, birds have feathers and aquatic mammals such as muskrats have an insulating layer of fur that prevents water from reaching the skin. This will affect absorption. On the other hand, other species like insects have exoskeletons, which are essentially coats of armor against absorption. However, insects have spiracles (i.e., tiny holes) in their exoskeletons through which they "breathe". Thus, chemicals are often more quickly and extensively absorbed in insects through their spiracles than they are in other species like humans.
• Cattle have four stomachs and within them as well as in the intestine they have a great amount of different bacteria. This impacts both absorption across the gut and metabolism of the chemical by bacteria, even before it is absorbed. For example, the cow will likely have a higher metabolic rate in the gastrointestinal tract (GIT) than a human. Therefore, the chemicals that are detoxified through metabolism, such as occurs by bacteria in the GIT, should be less toxic in cattle than in humans. However, the multiple stomachs and longer intestine means that the chemicals will be present in the GIT for a longer period of time than they would be in humans. This would tend to increase the absorption of the chemicals.
• Chocolate is toxic to dogs because they don´t have an enzyme that metabolizes it so that it can be excreted. Subtle differences in metabolic processes between species (e.g. mammals tend to have generally a metabolic capacity/rate one order of magnitude higher than other species like fish) can lead to major differences in susceptibility to the toxicity of a xenobiotic. This is a key question if we consider all metazoans, as the genetic background varies among groups.
• Anatomical and physiological differences can also impact excretion. For example, the kangaroo rat that lives in the deserts of Arizona and New Mexico is physiologically adapted to live without water. They can get enough water from their plant food to survive. This occurs because the kangaroo rat has a very efficient kidney that reabsorbs essentially all fluid that passed through the filter back into the bloodstream. Along with water, they also might reabsorb chemicals that would otherwise have been excreted. This could lead to increased retention of toxic chemicals and consequently, to a longer duration of chemical activity, which could increase the toxicity of a chemical relative to other species.

Note: It is difficult to extrapolate toxicity and potency across species based just on a couple of physiological differences. In reality, many physiological factors differ across species (e.g. respiration via gills in fish and lungs in other vertebrates).

3.2 GENETICS

The genetic makeup differs greatly among taxa and influences their susceptibility to chemical toxicity. This genetic variation impacts greatly chemical toxicokinetics and toxicodynamics affecting the degree of chemical accumulation and retention in the body, as well as its toxic effects, namely the impact signalling pathways and receptors.

Even within a single species, genetic differences can have profound effects on relative chemical toxicity. For example, the amount of acetyltransferase, an enzyme present in the liver to metabolize some chemicals, is genetically determined. If the levels of this enzyme are reduced, these chemicals will be metabolized more slowly and as a consequence, remain bioactive for a longer period of time. The result of the accumulation of these chemicals in the liver of people with slower metabolism can be liver toxicity. In some populations, such as African populations, up to 80% have lower levels of this enzyme. However, in other human populations, such as Eskimo and Japanese populations, the gene responsible for the slower metabolism is almost absent and consequently, the level of acetyltransferase is almost never affected.

3.3 GENDER AND HORMONAL STATUS

The toxicity of some chemicals may vary between females and males. Both the nature and location of toxic effects could be different in each sex. One of the critical factors that determine if a chemical might have different toxicity across sexes is a link between the metabolism of the chemical and sex hormones. Males often metabolize chemicals more quickly than females. In most cases, this leads to more resistance in the male because metabolism generally detoxifies a chemical. However, in the few cases where metabolism actually increases the toxicity of a chemical (e.g.: activation of PAHs), males may be more sensitive to the chemical than females. On the other hand, chemicals may exert different gender effects depending on the impact signalling pathways. For example, male fish are more susceptible to exposure to low levels of estrogenic chemicals than females.

Changes to hormonal status other than sex hormones (e.g.: hyperthyroidism) could increase sensitivity to a chemical. In humans, elevate levels of thyroid hormones can interfere with the male sex hormone actions on metabolism of chemicals. As a consequence, the benefit of faster metabolism is offset by the action of the thyroid. Chemicals that affect the hormonal status are referred to as endocrine disruptors, as reported in unit 4.

For more information on endocrine disruptors see the following links:

http://www.who.int/ceh/risks/cehemerging2/en/

http://www.niehs.nih.gov/health/topics/agents/endocrine/

3.4 NUTRITION AND DIETARY FACTORS

Deficiency of essential vitamins or nutrients can directly cause toxic effects. For example, lack of enough vitamin A reduces the ability of some enzymes from the cytochrome P450  system to metabolize chemicals, which could lead to increase toxicity. Additionally, the lack of available cofactors that are necessary in order for some metabolic reactions to occur or a low protein diet could also limit the amount of metabolic detoxification. On the other hand, poor nutrition (e.g.: starvation) might lead to mobilization of fat, which could release stored amounts of chemicals and lead to toxic effects.

Some essential elements such as zinc can protect against the absorption of toxic metals like lead when they are present in the GIT. This is because the two elements compete for absorption. In humans, zinc is favoured over lead by the active processes that occur in their intestines.

3.5 LIFE-CYCLE PHASE

It is generally agreed that, in the human case, the very young and the elderly are more sensitive to the toxic effects of chemicals. Many specific systems are not fully developed or mature in infants. This includes the blood-brain barrier, enzymes that metabolize alcohol, and much of the P-450 system of enzymes primarily responsible for metabolizing foreign chemicals. Because the defence mechanisms against chemicals are still not complete, chemical levels that would not lead to toxicity in adults could affect small children. On the other hand, the increased sensitivity in the elderly is likely due to the reduced activity of cells in general and enzymes in particular. This reduces the immunity of elderly people against both chemicals and infections. The metabolic efficiency of the liver is lower in the elderly and therefore, the chemicals are detoxified more slowly. Moreover, the number of storage compartments (e.g.: bone) where chemicals may be retained without toxicity may also be lower in the elderly.

Age also affects the rate of metabolism in fish because of growth and reproduction energy costs. Young fish require a large portion of energy for growth. Reproduction consumes a considerable amount of energy as well. Larger specimens will have a slower metabolism than their smaller counterparts.

In general, early life-cycle phases are more susceptible to environmental chemical than adults. For several endocrine disrupting chemicals, there are critical windows of development where sensitivity is elevated; for estrogenic and androgenic chemicals, fish are particularly sensitive during the sex-differentiation period, with a short-term exposure impacting the population sex ratio and/or gonad development (see unit 4).

Note: The different factors discussed above have a myriad of possible ramifications to the toxicity and potency of chemicals both across species and within a given species. The combination of these competing factors on toxicity and potency is the focus of the discipline of comparative toxicology.