The reasons a chemical, hazardous waste, pesticide, or air pollutant is regulated at a certain level or concentration is often linked to work performed by environmental toxicologists in the area of dose-response.

The science of dose-response is filled with uncertainties, extrapolations, and other dark areas resulting from a broad lack of knowledge about how people are affected by chemicals in the environment. The reality is that we are all surrounded and infiltrated by a great many chemicals. Within this toxic soup, zeroing in on a single chemical and asserting that a specific effect on health follows is beyond our current capability. Nonetheless, exact answers and perfect solutions are precisely what the public expects from government.

Dose-response is an evolving science, and answers and, perhaps, solutions will improve, assuming economic and political pressures do not interfere. Here are a few definitions and concepts to assist readers in understanding dose-response.

A dose-response relationship describes how the likelihood and severity of adverse health effects (the responses) are related to the amount and condition of exposure to an agent (the dose provided). Since it is impractical to study all possible relationships for all possible responses, toxicity research typically focuses on testing for a limited number of adverse effects.

Upon considering all available studies, the response (adverse effect), or a measure of response that leads to an adverse effect (called the precursor to the effect), that occurs at the lowest dose is selected as the critical effect for risk assessment. The underlying assumption is that if the critical effect is prevented from occurring, no other effects of concern will occur.

There is frequently a lack of dose-response data available for human subjects. When data are available, they often cover only a portion of the possible range of the dose-response relationship, in which case, extrapolation must be done to estimate dose levels that are lower than the range of data obtained from scientific studies. Animal studies are conducted to improve the data. However, such studies are controlled, meaning they do not account for confounding factors that occur in real-life conditions.

Also, dose-response relationships obtained from animal studies involve much higher doses than those found in people, so additional extrapolation to lower doses must be conducted to predict the relationship for humans. Dose-response investigations sometimes focus on the most sensitive members of the population. Therefore, regulatory efforts are generally made to keep exposures below the threshold for this population group.

A no-observed-adverse-effect level (NOAEL) is the highest experimentally determined dose without a statistically or biologically significant adverse effect. A reference dose (RfD) is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily oral exposure to the human population (including sensitive groups, such as asthmatics, or life stages, such as children or the elderly) that is likely to be without appreciable deleterious effects during a lifetime. A similar term, reference concentration (RfC), is used to assess inhalation risks.

Mode of action is the sequence of key events and processes to explain toxicity. Mode of action starts with the interaction of an agent with a cell, proceeds through operational and anatomical changes, and results in the effect, such as cancer formation. In the case of carcinogens, if the mode-of-action information is insufficient, a linear extrapolation is employed. In this type of assessment, there is theoretically no level of exposure for the chemical being assessed that does not pose a small but finite probability of generating a carcinogenic response.

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