Toxicology Primer

In order to understand adverse health effects of environmental agents it is essential to understand basic principles and definitions of toxicology.

Pharmacokinetics refers to the quantitative time course of toxins in the body and depends on absorption, distribution, biotransformation, and excretion.

Absorption of toxic chemicals by exposed individuals can occur via three different routes of entry.These include inhalation of fumes, vapors, and particulates into the respiratory tract; ingestion into the gastrointestinal tract; and dermal (skin) absorption of a liquid. Logically, the more volatile the compound, the more likely it is to be inhaled. Ingestion occurs in environmental situations, including water contamination and accidental or intentional ingestion. The more fat-soluble a compound, the more likely it is to be absorbed into the body by all three routes.

Chemical toxins can exert their effects at the point of entry with direct, local irritation; others are absorbed into the bloodstream and act at distal (distant) sites either by 1) direct toxicity to a susceptible target organ, 2) by sensitization or allergy, generally after multiple episodes of exposure, causing a reaction manifested by any or all of the following: skin rash, bronchospasm (an asthma-like picture), hypotension, and sudden death, or 3) by an idiosyncratic reaction which has to do with susceptibility based on the individual's genetic make-up; this type of reaction may initiate a cascade of biochemical and micro-anatomical changes that manifest in a toxic syndrome.

The distribution of a chemical toxin in the body is based on the charge/fat solubility, the size of the molecule or ion, and its interaction with naturally occurring enzymes, protein carriers and other chemicals in the body. A toxin's distribution greatly influences its toxicity. For example, some chemicals are absorbed by organs they do not damage(like lead in bone), thereby reducing their effective circulating dose in the body. Others concentrate in their target organ, where they exert their adverse effects.

Many chemicals undergo biotransformation in the body by existing enzyme systems. This process can render them more or less toxic, and can form charged or uncharged molecular structures which determine how a given chemical will be handled by the body. Fat-soluble molecules may bioaccumulate, or concentrate, in fatty tissues of the body where quantity can grow over time; a stressor, such as rapid weight loss, can cause a sudden increase in circulating levels of toxicants in the body.

The more rapidly a chemical is eliminated from the body, most frequently in the kidney or GI tract, the less time it has to exert its toxic effect. The elimination half-life refers to the amount of time required for excretion of half the internal exposure concentration. Fat soluble substances, which tend to be absorbed fatty tissue, are less available for excretion. They may be excreted slowly over time, and only if transformed to a water-soluble product.

Acute toxicity refers to short-term adverse health effects; chronic toxicity refers to exposure over a period of time which results in delayed toxic manifestations. The occurrence of the latter is presumably due to accumulation of dose over time or to the eventual over-ride of the host's (exposed individual's) natural defense mechanisms.

The quantity and duration of exposure determine the dose assumed by the host. In general, there is a dose-response relationship between toxin exposure and symptom or disease manifestation, i.e., the greater the dose, the more likely an adverse effect will be seen (and the more severe the effect, as the dose increases). For many chemicals, there appears to be a threshold, frequently expressed in milligrams (or quantity) of toxin per kilogram of the host's body weight, above which toxic effects are first manifested. This threshold value is best described for pharmaceuticals which have been carefully tested in animal models as well as humans; for industrial or environmental chemicals, this threshold is derived from animal studies and from case reports of intoxicated humans where exposure levels have been known. There may not be a threshold below which carcinogenicity (cancer-causing mutations) will not occur.