Toxic Tuesdays

How Individual Variability Affects the Toxicity of Chemicals

Toxic Tuesdays

CHEJ highlights several toxic chemicals and the communities fighting to keep their citizens safe from harm.

How Individual Variability Affects the Toxicity of Chemicals

It’s clear that not everyone responds to the same chemical exposures in the same way. There are many examples of this. The most striking is the person who smoked cigarettes for 30 years and never had breathing problems or developed lung cancer.  A major factor in why this happens is “individual variability.”

People process chemicals differently depending on internal factors. There are two major sources of variability in people. The first is variability in the penetration of a chemical to the target organ, referred to as pharmacokinetics. The second factor is the response of the target organ and biological system itself, referred to as pharmacodynamics. Pharmacokinetics is relatively well understood compared to pharmacodynamics.

There are four sources of variability in people: uptake, distribution, metabolism and excretion. Uptake of chemicals through breathing, referred to as respiratory absorption, is mainly influenced by the solubility of the chemical in the blood and its interaction with the respiratory surfaces in the lungs. The solubility of a single chemical in the blood can differ significantly from one person to another. Solubility in the blood can even change in a single person depending on food intake and diet. How much uptake occurs alters the concentration of a chemical in the body which in turn alters its toxicity. Similarly, dermal absorption, or uptake through the skin, depends on the exposed site, the condition of the skin, and the humidity and temperature of the environment. Uptake through the stomach, referred to as gastrointestinal absorption, depends primarily on stomach content.

The distribution of chemicals in the body is also highly variable and depends primarily on body size and composition. Chemicals that are soluble in fat, for example, will be distributed differently in people with different amounts of fat. Distribution is also affected by the degree to which a chemical can bind to molecules, mostly proteins, in the body. The amount of a chemical bound to proteins in a target organ determines how much damage a chemical can cause. Chemicals that are not bound in the body are more easily removed. Chemical binding can be altered if there’s competition for binding sites due to the presence of other chemicals or drugs in the blood system.

Metabolism plays a central role in how the body responds to a chemical and is probably the most important source of pharmacokinetic variability in people. The body has different ways it can interact with or metabolize a chemical. This interaction helps determine the body’s response to chemicals. In some instances, a chemical can become more toxic and in other instances, it can become harmless. Metabolism mainly takes place in the liver but can also occur in the skin and lungs. Metabolism can be altered by several environmental factors. For example, the simultaneous absorption of chemicals in high doses can slow metabolism because of competition for the metabolizing enzyme in the body. Genetic factors also play an important role in metabolizing toxic chemicals. Individual variability in genes results from differences in the DNA sequence of genes (called polymorphisms). These individual differences play an important role in a person’s response to chemicals such as in the development of cancer. Metabolism can also be affected by age and sex, environment, chemical intake, physical activity, protein binding and lifestyle.

Once a chemical has been absorbed, distributed, and metabolized, it will be excreted from the body. The primary way that the body excretes toxic chemicals is through the kidneys. Some excretion may also occur through the lungs, GI track, skin and mammary glands in pregnant women. Renal excretion is influenced by factors such as kidney function, protein binding, urine pH and urine flow, which also varies in individuals. Volatile chemicals, chemicals with a tendency to evaporate, are generally excreted by the lungs. Pulmonary excretion is determined by the same factors that influence pulmonary absorption.

These many sources of variability mean that two people can be exposed to the same concentration of a chemical but absorb, distribute, metabolize and excrete it differently resulting in a different response. This is why scientists and government health officials struggle to explain what will happen to a group of people exposed to the same mixture of chemicals. A person’s response is highly complex and the scientific understanding of how different variables influence toxicity is not well developed. These gaps in our knowledge reflect the many uncertainties in how chemicals produce their toxic effects on the human body.  

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