A Theoretical Approach to the Ferguson Principle and its Use with Non‐Reactive and Reactive Airborne Chemicals

Abstract

Abstract:The Ferguson principle has been widely used in toxicology to separate or indicate possible mechanisms for acute toxic effects of chemicals. However, this principle has never been adequately tested because of the lack of a database containing a sufficient number of both types of chemicals, non-reactive and reactive, that the Ferguson principle purports to separate. Such a database is now available. In this report a theoretical framework for the Ferguson principle is presented, regarding one of the acute toxicological effects of volatile airborne chemicals: sensory irritation. Previously obtained results on series of non-reactive and reactive chemicals are then used to demonstrate that the Ferguson principle can be extended to reactive chemicals by adding chemical reactivity descriptors to the physicochemical descriptors required by the Ferguson principle. This approach can be successful, provided that specific chemical reactivity mechanisms can be identified for the reactive chemicals of concern. The findings suggest that it is possible to replace the empirical Ferguson principle by formal mechanistic equations which will provide a better foundation for the understanding of the mechanisms by which airborne sensory irritants exert their action.It has been shown (Ferguson 1939;Brink & Posternak 1948;Ferguson 1951; Abraham el al. 1994) that the ratio PRO may be approximately constant (the "Ferguson rule or principle'') for non-reactive volatile organic chemicals giving rise to a particular biological effect. P is the vapour pressure (mmHg or ppm), i.e., the concentration in air of the chemical necessary to induce a given level of effect. P" (same units) is the saturated vapour pressure of the pure liquid. This approach was taken by Ferguson (1939) to demonstrate that toxic indices based on PRO would lie within a relatively narrow range (approximately a constant) for nonreactive chemicals while the measured concentrations, P, would vary widely since the phase distribution phenomenon is not taken into account when using only I?With a P/Po ratio of >0.1 or so, the mechanism by which a chemical induces the biological effect has been defined as physical: due to weak forces attraction between the chemical and the receptor biophase. A ratio <0.1 would indicate a chemical reaction, although physical mechanisms still play a role. This rule could never be tested in a satisfactory manner until recently. Using a database of 145 volatile organic chemicals inducing the same biological effect, i.e., sensory irritation, it has been demonstrated that the above rule, when used to divide the database into 56 non-reactive and 89 reactive (electrophiles) chemicals, can definitely be a good starting point (Alarie et al. 1998) as originally proposed by Ferguson (1939).

Molecular restrictions for human eye irritation by chemical vapors

“…We have hypothesized that the chemesthetic potency of non-reactive VOCs (Alarie et al, 1998), that is, VOCs unlikely to damage mucosal tissue simply upon a brief vapor exposure, would rest heavily on "selective" or "transfer" processes rather than on chemically-and structurally-restricted "specific" interactions. In agreement with this line of thought, a solvation equation (Abraham, 1993;Abraham and Weathersby, 1994) that models transfer processes across biological matrices successfully described and predicted human psychophysical thresholds for nasal pungency ) and eye irritation , obtained under standardized conditions, for four dozen or more chemically diverse VOCs.…”

Chemosensory additivity in trigeminal chemoreception as reflected by detection of mixtures

“…Many of these VOCs are relatively nonreactive vapors (cf. Alarie et al 1998), unlikely to damage mucosal tissue simply upon brief vapor exposure. Still, despite their enormous diversity in chemical structure (Cometto-Muñiz 2001) and their nonreactive nature, they produce mucosal sensory irritation.…”

Chemical activity as an integrating concept in environmental assessment and management of contaminants

“…The ''Ferguson Principle,'' a strong correlation between chemical activity and the onset of narcosis, has been discussed and tested by other workers, notably Brink and Posternak (1948), Abraham et al (1994) and Alarie et al (1998), as well as Ferguson and Pirie (1948). The Principle has also been termed the Brink-Posternak-Ferguson (BPF) Rule.…”