Toxic Dose

One of the major principles in toxicology is that the potency of the poison, as well as its mode of action, are largely determined by the dose (per body weight) to the organism ingesting the poison. It is often said in fact that the dose makes the poison. This means that at low-enough exposures, most chemicals have no negative effects, although at very high exposures, many chemicals, even those that one would not usually consider to be hazardous, may in fact be toxic. Some poisonous compounds, both natural and man-made, kill at high doses, cause chronic illness or systemic effects at lower doses, and are either harmless or even required at very low doses.

A good example is arsenic, which was a killing poison of choice throughout a good deal of human history. At the levels found in the modern environment, arsenic toxicity rarely results in acute injury or death, but various other chronic diseases, including some types of cancer, have been associated with chronic low levels of human exposure. However, at even lower concentrations, arsenic is a natural component of many foods and may be an essential element for several types of animals, as are other metals such as zinc and copper. Another example is lead, which as we will see in detail in chapter 9 is lethal at high doses, causes severe and recognizable illness at lower doses, and at even lower doses causes fairly subtle defects in cognitive functioning. Lead and mercury are both dangerous at almost any level of exposure.

One of the most important principles of toxicology is that of the dose-response relationship, which is central in environmental health and toxicology and is a very complex subject (see figure 4-1 for examples). In general we can say that the higher the exposure or dose, the greater the risk. In figure 4-ia, for instance, we see three lines, each of which shows a dose response. One line goes through the origin, indicating that at zero dose there is no effect, but at all doses above zero there is some effect. The other two lines do not go through the origin, either because there is a threshold at low doses or because there is some effect in the absence of exposure.

The curve in figure 4-ib includes both a threshold (or no-effect) dose and a saturation at high dose. Figure 4-ic shows a similar curve without any threshold.

The simplest shape of a dose-response curve is a straight line. If doubling the dose doubles the risk, then we say that there is a linear dose re-

Figure 4-1. Dose-response curves.

LINEAR DOSE-RESPONSE CURVES

LINEAR DOSE-RESPONSE CURVES

AN S-SHAPED DOSE-RESPONSE CURVE
DOSE RESPONSE WITHOUT A THRESHOLD
DOSE

sponse with a slope of one (see figure 4-ia). Things are not usually this simple. The precise quantitative relationship between dose and response, that is, between exposure and risk, is usually much more complex. Figure 4-ib shows a more typical dose-response curve. There are two parts of the relationship that are particularly important, one at the very low end of the exposure spectrum, and one at the high end. For the vast majority of toxico-logical effects by chemicals, there exists an exposure level that is called the threshold. Some scientists refer to it as the toxic threshold value, or no-effect level, or no-observable-effect level (NOEL). All these terms mean the same thing, namely that for almost all chemicals if the dose is very low, there will be no effect. In figure 4-ib, this is shown by the arrow marked "threshold." Below the dose indicated by this arrow, the effect of the toxic exposure is null. Thresholds exist for all common poisons such as arsenic (which, as mentioned, may actually be beneficial to one's health at very low levels) and for virtually all chemical pollutants.

The great exception to the threshold rule is carcinogenesis. Figure 4-ic shows how a dose-response curve for a carcinogen or other chemical with no threshold for toxicity might look. Notice that there is no point above zero exposure that gives no effect. In other words, for any level of exposure at all, no matter how small, there is some effect, even if very small. This is a very controversial issue, but there are strong theoretical and experimental arguments that support the idea that for many categories of chemical carcinogens there is no threshold, and that a certain degree of risk, even if very small, exists for exposure to the smallest possible level of carcinogenic chemicals. One of the goals of environmental toxicologists is to determine the NOEL for chemicals. Many regulatory rules and standards are based on such levels.

This question of safe or no-effect dosage is a critical scientific problem in understanding the health risk from toxic chemicals. As regulations and improved safety and cleanup measures have taken effect, and as exposure levels continue to drop, when do we know if we've reached a safe level of exposure? It seems logical to think that when no more of the chemical can be detected there cannot be any more exposure. But analytical techniques to measure even tiny amounts of chemicals have become so sensitive that it is possible to find some infinitesimal amount of almost every chemical practically everywhere.

When a new technology or improved analysis method is used to investigate pollution levels, the lower limit of detection goes down, and it becomes possible to measure ever-lower levels of chemicals and compounds. So the same level of contamination that used to be classified as "below detection'' might later register as 45 ppb (45 parts per billion, or 0.000000045). This level of a compound, although now detectable, may or may not represent a health hazard, but the fact that technology has improved to the point where it can accurately be measured does not mean that its presence in the environment has gone up.

It therefore becomes necessary to set exposure standards based on the expected or predicted health effects of that exposure level. This is not an easy task. It is one thing to say that chemicals like mercury, arsenic, nitrogen oxides, or ozone are toxic. But it takes a lot of careful research to be able to say that a particular dose of that chemical is not toxic because it falls under the threshold required for toxicity.

At the high end of the exposure scale, one finds the phenomenon of saturation (see figure 4-ib). This means that when the exposure level reaches a certain value, the risk is so high that any further increase in exposure has no effect. To illustrate this, suppose you give someone a gram of cyanide. Death is virtually certain at this dose. If you increase the dose to 10 grams or 100 grams, there is no increase in the risk of death, which was already at the maximum level. Saturation can occur at levels of risk below certainty. There is probably a saturation effect of cigarette smoking, so that smoking three packs a day or six packs a day both result in about a 25 percent chance of getting lung cancer. It is very important to understand that saturation occurs only at very high levels of exposure, where further increases in exposure do not produce any further increases in risk.

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